• astrocytes;
  • BDNF;
  • GABA;
  • glutamate;
  • serotonin


  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References

The association of temporal lobe epilepsy with depression and other neuropsychiatric disorders has been known since the early beginnings of neurology and psychiatry. However, only recently have in vivo and ex vivo techniques such as Positron Emission Tomography, Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in combination with refined animal models and behavioral tests made it possible to identify an emerging pattern of common pathophysiological mechanisms. We now have growing evidence that in both disorders altered interaction of serotonergic and noradrenergic neurons with glutamatergic systems is associated with abnormal neuronal circuits and hyperexcitability. Neuronal hyperexcitability can possibly evoke seizure activity as well as disturbed emotions. Moreover, decreased synaptic levels of neurotransmitters and high glucocorticoid levels influence intracellular signaling pathways such as cAMP, causing disturbances of brain-derived and other neurotrophic factors. These may be associated with hippocampal atrophy seen on Magnetic Resonance Imaging and memory impairment as well as altered fear processing and transient hypertrophy of the amygdala. Positron Emission Tomography studies additionally suggest hypometabolism of glucose in temporal and frontal lobes. Last, but not least, in temporal lobe epilepsy and depression astrocytes play a role that reaches far beyond their involvement in hippocampal sclerosis and ultimately, therapeutic regulation of glial-neuronal interactions may be a target for future research. All these mechanisms are strongly intertwined and probably bidirectional such that the structural and functional alterations from one disease increase the risk for developing the other. This review provides an integrative update of the most relevant experimental and clinical data on temporal lobe epilepsy and its association with depression.

Abbreviations used





antiepileptic drug


brain derived neurotrophic factor


corticotropin-releasing factor






metabotropic glutamate receptors


Magnetic Resonance Imaging


Magnetic Resonance Spectroscopy


positron emission tomography


serotonin re-uptake inhibitor


temporal lobe epilepsy

Introductory remarks on human temporal lobe epilepsy and depression

  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References

Incidence and clinical symptoms

Temporal lobe epilepsy (TLE) is the most frequent of the epileptic disorders, and depression, being more common and severe in epilepsy than in other medical or neurological conditions (Harden 2002; Harden and Goldstein 2002; Kanner 2006a,b), has an especially strong association with TLE (Blumer et al. 1995; Altshuler et al. 1999; Yamamoto et al. 2002; Kanner 2006a). The lifetime incidence of depression among patients with chronic epilepsy is 30% (Hermann et al. 2000); however, its prevalence in patients admitted to a tertiary epilepsy center is as high as 50% (Kanner 2003; Boylan et al. 2004). Patients suffering from refractory TLE report that depression has a greater negative impact on quality of life than the number of prescribed antiepileptic drugs (AEDs) or seizure frequency (Gilliam et al. 2003; Boylan et al. 2004; Pulsipher et al. 2006). In line with this, the incidence of suicide and suicidal ideation is increased in epileptics in general and in those with TLE in particular (Baker 2006; Pompili et al. 2006).

Feelings of despair, depressive mood, aggressive behavior, anxiety, memory impairment and overt psychosis are among the common psychiatric features in patients with TLE (Kanner and Balabanov 2002; Blumer et al. 2004). Symptoms can occur before, during, after and in between seizures, and usually differ in severity, duration and response to treatment. Mood disturbances often are compatible with a diagnosis of major depression, but they are sometimes more pleomorphic and may have a more abrupt start in epileptics than in non-epileptics (Blumer et al. 2004). Additionally, it is well-described, although somewhat controversial, that temporal lobe seizures may lead to permanent personality changes with rigid, narrow-minded behavior combined with a triad of hyperreligiosity, hypergraphia and hyposexuality (Wuerfel et al. 2004). However, antiepileptic treatment is not only efficacious in preventing seizures in TLE, but aberrant emotional behavior is frequently normalized as well. Indeed, in people with or without epilepsy, anticonvulsants are mood-stabilizing. AEDs such as carbamazepine, valproate and lamotrigine are well-established in treating patients with bipolar affective disorders (Gajwani et al. 2005). Phenytoin decreases impulsive aggression in both criminal and non-criminal individuals (Stanford et al. 2005). Further, vagus nerve stimulation, a non-medical treatment for refractory epilepsy, is now also a therapeutic tool in depression (Ben-Menachem 2001; Labiner and Ahern 2007); and although not always (Malmgren et al. 2002; Asztely et al. 2007), depression and anxiety associated with refractory TLE may improve after epilepsy surgery (Devinsky et al. 2005; Alonso et al. 2006; Pintor et al. 2007). Apart from psychological factors, removal of dysfunctional limbic areas probably has direct impact in alleviating psychiatric symptoms (Reuber et al. 2004).

Both intrinsic-biological and extrinsic-psychological factors have been suggested to cause the association of TLE and depression, and obviously, a multi-factorial explanation is likely. Evidence is arising that the relation between epilepsy and psychiatric disorders may not be strictly unidirectional, but bidirectional (Yamamoto et al. 2002; Kanner 2006a,b; Spencer 2007). Thus, epilepsy may lead to depression – and vice versa. Indeed, several studies confirm that depression and suicide attempts are independent risk factors for the onset of seizures and epilepsy (Forsgren and Nystrom 1999;Hesdorffer et al. 2006). Depression raises the risk 1.7 fold and suicidality five fold (Hesdorffer et al. 2006). In the elderly, major depression has an even stronger association with newly onset of unprovoked seizures and increases the risk six fold (Hesdorffer et al. 2000). A preliminary explanation may be that the functional and structural changes occurring in depression lower the seizure threshold and thereby provoke epilepsy. As will be discussed comprehensively in this review, more and more data suggest the intriguing idea that TLE, depression and possibly other neuropsychiatric disorders such as anxiety may share common pathogenic mechanisms (Fig. 1). These mechanisms are probably strongly intertwined and the structural and functional alterations from one disease may trigger the other.


Figure 1.  Schematic depiction of pathophysiological mechanisms in temporal lobe epilepsy and depression. As indicated by the arrows these mechanisms are probably bidirectional such that the structural and functional alterations from one disease may evoke the other and vice versa. Note that all items are arranged according to their occurrence on a molecular, cellular or global level, independent of relative importance.

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Neuroanatomical findings

Brain regions involved in both TLE and depression include the temporal lobes with hippocampus, amygdala, entorhinal and neocortical cortex; the frontal lobes; subcortical structures such as basal ganglia and thalamus; and the connecting pathways (Sheline 2003; McEwan 2005; Lavretsky et al. 2007; Mueller et al. 2007). Thus, although hippocampus and amygdala have received the greatest interest, extralimbic structures are affected as well. In both depression and TLE, for instance, smaller volumes of frontal lobes have been found (Lavretsky et al. 2007; Mueller et al. 2007). However, TLE may roughly be divided into two categories: Mesial TLE with the hallmark of hippocampal sclerosis is very common, and neocortical TLE due to focal cortical dysplasia or microdysgenesis is relatively rare. Patients with mesial temporal sclerosis show significantly higher depression scores than patients with neocortical temporal lesions, independent of the lateralization of the lesion (Quiske et al. 2000). Moreover, compared to TLE patients without hippocampal sclerosis, patients with mesial TLE have greater frequency of cognitive side effects and mood disturbances when treated with AEDs (Mula et al. 2003). Mesial TLE, characterized by neuronal cell loss in specific hippocampal areas, gliosis, microvascular proliferation, and synaptic reorganization (Cavazos and Cross 2006), may also coexist with neocortical TLE. This ‘dual pathology’ (Cendes et al. 1995) often leads to especially severe and refractory seizures, which explains why between 10% and 87% of all patients undergoing temporal lobe resection suffer from this condition (Ho et al. 1998; Kuzniecky et al. 1999; Li et al. 1999). High-resolution Magnetic Resonance Imaging (MRI) studies of depressed individuals with and without TLE have found decreased volumes of the hippocampus (Gascino et al. 1991; Sheline et al. 1996, 1999; Bremner et al. 2000; Sheline 2003; Baxendale et al. 2005). Only few studies have failed to support these findings (Richardson et al. 2007). Hippocampal volumes in depression are decreased bilaterally (Sheline et al. 1996, 1999; Sheline 2003) or in the left hippocampus only (Bremner et al. 2000). In TLE, volumes may be reduced on the site of seizure origin (Gascino et al. 1991; Baxendale et al. 2005; Mueller et al. 2007) or, when combined with depression, bilaterally (Baxendale et al. 2005). In patients with TLE of left origin, depressive symptoms are associated with greater impairment of memory and learning (Dulay et al. 2004). This is possibly because of involvement of hemispheric language representation. Indeed, other authors have confirmed a relationship between depression and impairment of verbal learning for TLE patients with left-sided pathology, and between depression and figural learning deficits for right temporal pathology (Helmstaedter et al. 2004).

Next to the hippocampus, the temporal lobe structure having received greatest attention is the amygdala, which plays a major role in the processing of fear and related emotions (Phelps and LeDoux 2005). This region seems to undergo a two-staged process with initial bilateral enlargement during acute and a subsequent shrinkage during chronic depression. Patients with TLE complained of greater depressive symptoms with increasing amygdala volumes measured by MRI (Richardson et al. 2007). This finding confirmed earlier reports by Tebartz van Elst et al. (1999). Moreover, the latter authors found a significant correlation between left amygdala volume and depression severity (Tebartz van Elst et al. 1999, 2000). Thus, the amygdala is hyperactive in anxiety and mood disorders and may increase in size during acute depression in patients with TLE (Tebartz van Elst et al. 1999; Richardson et al. 2007) and without epilepsy (Frodl et al. 2002). This transient enlargement may be secondary to enhanced regional blood flow and vascular volume as detected by positron emission tomography (PET) (Drevets 2000) or because of dendritic remodeling with increased branching of amygdaloid neurons (Vyas et al. 2002). However, amygdala volumes are, similar to hippocampal volumes, decreased in recurrent and chronic depression (Sheline et al. 1998; McEwan 2005). In contrast, unchanged amygdala volumes, but right hippocampal atrophy, were noticed in refractory TLE associated with chronic personality changes such as hyperreligiosity (Wuerfel et al. 2004).

Animal behavior in models of temporal lobe epilepsy and depression

  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References

Overview of animal models with a comment on their validity

As TLE and depression evoke emotional and cognitive features commonly regarded as purely human, some general considerations on the modeling of these disorders seem mandatory. Criteria for establishing animal models of neuropsychiatric disorders include face validity (how well is human behavior copied by the animal model?), causative or construct validity (how well does the factor, which induces the modeled behavior, correspond to current pathophysiological theories?) and predictive validity (how well does the model predict the therapeutic activity of drugs used to treat the disorder in humans?). Face validity is often difficult to achieve. Only some symptoms can be imitated such as fatigue and decreased sexual drive, but not the feeling of guilt for example. Causative validity is hard to realize as well, as our knowledge about many of the underlying causes of brain disorders are still very limited. Predictive validity may be the most important criteria, because animal models with high predictive validity are the ones used in pharmacological research. Models of epilepsy or depression have high predictive validity when they respond to the same pharmacological treatment used in humans, but not to other drugs. For these reasons, animals are evaluated for particular aspects of depression such as anxiety, aggression, memory impairment, stress intolerance, psychomotor disturbances and response to antidepressant drugs. Behavioral tests such as the forced swim test are valuable in predicting potential antidepressant properties of new substances (for reviews see D’Mello and Steckler 1996; and Matthews et al. 2005).

Some of the best-studied TLE models use the convulsants kainate and pilocarpine, which can be administered stereotactically into the temporal lobe or systemically. In contrast to systemic administration, direct injection into the temporal lobe does not lead to brain lesions outside this area. The great advantage of the kainate and pilocarpine models is their good face validity in that spontaneous seizures develop after a latency period of several weeks following an initial temporal lobe damage provoked by status epilepticus (Coulter et al. 2002). Frequency and severity of spontaneous seizures in kainate or pilocarpine treated rats are characterized by great inter-subject variability. Labor-intensive video-monitoring and eventually EEG-monitoring are necessary. Subtle partial seizures might frequently be missed. Another TLE model is electrical kindling. It has been shown that electrical amygdala kindling is more efficient in increasing emotional reactivity than kindling of hippocampus or caudate nucleus (Kalynchuk et al. 1998). However, face validity is low, as seizures do not occur spontaneously, hippocampal sclerosis does not develop and there is no real period of latency between the noxious stimulus and seizure development. For an overview on animal models of TLE see Coulter et al. (2002). TLE models have been studied quite extensively regarding anxiogenic- and depressive-like symptoms and memory impairment (Depaulis et al. 1997; Kalynchuk 2000). Note that all these studies differ with respect to the applied models, frequency of kindling and time of testing.

Depression-like behavior, anxiety and memory impairment

Rats with short-term amygdala kindling performed as well as controls on tests of depression such as the saccharose-preference test or the forced swim test (Helfer et al. 1996). In contrast, exploratory behavior was decreased (Adamec and McKay 1993; Adamec and Morgan 1994; Helfer et al. 1996). Immobility during social interaction (Helfer et al. 1996), corticotrophin releasing factor-induced defensive fighting (Weiss et al. 1986), stress-induced gastrointestinal ulcers (Henke and Sullivan 1985) and predatory aggression were increased (McIntyre 1978). Moreover, amygdala kindling increases anxiety-like behavior in rats (Adamec and Young 2000), and phenytoin reduces isolation-induced aggression (Keele 2001) suggesting that, as will be described later, epilepsy-like hyperexcitability in the amygdala is involved in abnormal emotional behavior. Increased anxiety in the elevated-plus maze was also found in adult rats with TLE secondary to prolonged experimental febrile seizures on postnatal day 10 (Mesquita et al. 2006). These rats did not show depression-like behavior other than increased anxiety. In contrast, rather surprisingly, a five-month period of TLE induced by pilocarpine decreased anxiety of adult rats in the elevated-plus maze (Detour et al. 2005; Dos Santos et al. 2005). Similarly, pilocarpine rats showed increased exploratory activity in the open-field test, suggestive of lower anxiety levels (Dos Santos et al. 2005; Szyndler et al. 2005). However, when rats received both pilocarpine and cycloheximide, which influences synaptic reorganization resulting from pilocarpine-induced status epilepticus, the anxiolytic effects vanished (Dos Santos et al. 2005). As discussed below, these findings probably suggest that electrical and chemical kindling can up- and down-regulate fear processing pathways in the amygdala and other parts of the limbic system leading to increased or decreased anxiety.

Rats with short-term amygdala kindling performed normally on tests of spatial memory (Nieminen et al. 1992; Letty et al. 1995). Likewise, no impairment in spatial and working memory tasks was observed in adult rats with TLE secondary to prolonged hyperthermic seizures (Mesquita et al. 2006). Long-term electrical kindling, however, decreased performance in the Morris water maze (Cammisuli et al. 1997) as did induction of TLE by pilocarpine (Hort et al. 1999; Dos Santos et al. 2005). Similarly, Wu et al. (2001) reported deficits in the Morris maze and radial arm maze test in lithium–pilocarpine treated rats. Cognitive impairment in this model was also indicated by decreased immobility and freezing time in contextual and tone fear conditioning (Dos Santos et al. 2005).

Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions

  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References

Neuronal hyperexcitability

Growing evidence suggests that limbic seizures in humans and rats lastingly modify the activity of neuronal circuits involved in anxiety and anxiety-related behavior (Depaulis et al. 1997; Hughes and Keele 2006). Hyperexcitability of the amygdala has been proposed as a possible mechanism. Increased excitability appears to play also a critical role in reciprocal pathways between the central nucleus of the amygdala and the periaqueductal gray matter, which modify fear-motivated reactions (Bruchey et al. 2006). It is noteworthy in this context that, as stated above, some MRI studies have confirmed larger amygdala volumes in patients with TLE and depression (Tebartz van Elst et al. 1999; Richardson et al. 2007). Mossy fiber sprouting, gliosis, and synaptic reorganization in the hippocampus, amygdala, parahippocampal cortices and thalamus during temporal lobe seizures may participate in the constitution of hyperexcitable circuits underlying spontaneous seizures and emotional disturbances (Roch et al. 2002). In line with this, amygdala kindling increases anxiety-like behavior in rats (Adamec and Young 2000) and results in significant reduction of long-term potentiation in the hippocampus, possibly leading to memory disturbances at the same time (Schubert et al. 2005). Antiepileptic agents reduce aggression in rats (Keele 2001) and humans (Stanford et al. 2005). Indeed, when anticonvulsant treatment is effective in controlling seizures in TLE, abnormal emotional behavior is often normalized, too. Also in patients without epilepsy, anticonvulsants are mood-stabilizing and often used to treat bipolar affective disorders. All this evidence suggests that epilepsy-like hyperexcitability in the amygdala and other temporal lobe regions is involved in disturbed emotional behavior (Hughes and Keele 2006). Conversely, it can be hypothesized that repeated depressive episodes may have a kindling effect by successively lowering the seizure threshold until unprovoked seizures occur. Thus, cellular and molecular mechanisms producing epileptic hyperexcitability in the amygdala and other limbic regions may at subseizure levels contribute to emotional dysfunction. In its most severe form, however, neuronal hyperexcitability is expressed as seizure activity. Neurons in epileptic tissue continuously discharge bursts of action potentials termed paroxysmal depolarization shifts. It has been shown that up-regulation of Ca2+-current in sclerotic hippocampi alters persistent sodium current, and sodium channel subtype composition contribute to hyperexcitability in TLE (Vreugdenhil et al. 2004). Moreover, increased conductance mediated by NMDA receptors and enhanced mRNA levels of NMDA receptor subtypes have been demonstrated in dentate granule cells in resected human hippocampi (Lieberman and Mody 1999). Altogether, this points to enhanced glutamate-mediated hippocampal transmission in TLE. Glutamate receptor expression is also altered in mood disorders. Beneyto et al. (2007) reported an increased NMDA receptor binding in hippocampus in major depression and bipolar disorder. Thus, TLE and depression may share disturbed glutamate-mediated transmission in the medial temporal lobe.

Disturbances of glucose metabolism

PET imaging studies of glucose metabolism and cerebral blood flow in patients with TLE and depression have so far mainly focused on frontal and temporal lobes, with hippocampus and amygdala being the regions of main interest. In TLE, most studies using interictal fluorodeoxyglucose-positron emission tomography (FDG-PET) have confirmed hypometabolism of epileptogenic temporal regions (Manno et al. 1994) such as the hippocampus (Semah et al. 1995), often bilaterally (Joo et al. 2004; Kim et al. 2006). A specific deficiency of complex I of the mitochondrial respiratory chain in the hippocampal CA3 region has been demonstrated by Kunz et al. (2000) in TLE patients with a hippocampal epileptic focus. Also Kann et al. (2005) showed severe metabolic dysfunction in the hippocampus in chronic epileptic humans and rats during neuronal activation. Results from these studies demonstrate mitochondrial enzyme defects and provide a cellular correlate for hypometabolism in TLE. Hypometabolism is usually more extensive than the underlying anatomic abnormality (Casse et al. 2002; Henry and Votaw 2004; Mauguiere and Ryvlin 2004). Even without a structural lesion FDG-PET hypometabolism is seen in significant areas of the temporal lobe (Semah 2002; Vinton et al. 2007). The amount of resected hypometabolic tissue is positively correlated to outcome after temporal lobe surgery (Vinton et al. 2007). Hypometabolism occurs also outside the seizure focus, often involving frontal regions (Semah 2002), and appears to be associated with poorer seizure outcome after surgery (Choi et al. 2003). In depression, FDG-PET (Mayberg 2003) has revealed comparable hypometabolism in the orbitofrontal, dorsolateral and ventrolateral prefrontal cortex. These findings confirm data from previous experiments but are somewhat contradictory in that some earlier studies additionally showed an increased metabolism and blood flow in parts of the orbital cortex and in the amygdala (Drevets 2000). Also in TLE and comorbid depression, the data are still relatively unclear. The few existing PET studies of TLE patients with depression allow only preliminary conclusions (Bromfield et al. 1992; Victoroff et al. 1994; Semah 2002; Salzberg et al. 2006; Richardson et al. 2007). Some groups have found unchanged temporal lobe glucose metabolism in TLE in the presence or absence of depression (Bromfield et al. 1992; Richardson et al. 2007). Others did find an association between major depressive episodes and decreased glucose metabolism of temporal lobes (Victoroff et al. 1994). Bromfield et al. (1992) observed lower metabolism additionally in the inferior frontal cortex in TLE patients with high depression scores compared to less depressed patients and healthy volunteers. Indeed, orbitofrontal hypometabolism of glucose has been suggested as a predisposing risk factor for the development of depression in patients with TLE (Salzberg et al. 2006). The relevant mechanisms may include extension of sclerosis and cell loss from the temporal lobe to extratemporal structures (Semah 2002) or compensatory neuronal inhibition (Salzberg et al. 2006). Alternatively, orbitofrontal hypometabolism may come secondary to depression or may just be a marker for general cerebral dysfunction associated with TLE (Salzberg et al. 2006). In depression without epilepsy, increased blood flow and glucose metabolism have been reported in the amydgala in some studies (Drevets 2000), but this has not been found in patients with combined TLE and depression (Salzberg et al. 2006; Richardson et al. 2007). Possibly, AED medication and developing hippocampal sclerosis may decrease amygdaloid glucose metabolism in TLE. Differences of study protocols and time points of measurements may also explain the discrepancy, as the amydala in depression, as explained above, seems to undergo a dynamic process with initial enlargement (Frodl et al. 2002) and subsequent shrinkage (Sheline et al. 1998; McEwan 2005). Alternatively, elevated amygdaloid activity may just not be essential to the development of depressive symptoms.

In conclusion, whereas PET findings in depression have been somewhat contradictory, in TLE hypometabolism in temporal and frontal lobes has been well-described. Dysregulation of glucose metabolism in orbitofrontal cortex, already involved in non-epileptic depression, may also play a role in mood disturbances associated with TLE.

Serotonin and other monoaminergic neurotransmitters

Imaging studies of serotonin metabolism

Abnormalities of serotonin (5-HT) transmission have well-known implications for both depression and TLE (Spencer 2007). Several PET studies on 5-HT transmission have been performed in TLE patients with (and without) depression. Decreased binding to 5-HT1A receptors has been found in the amygdala, hippocampus, temporal cortex, insula, anterior cingulate and the raphe nucleus of the side of seizure origin and in the opposite hippocampus (Toczek et al. 2003; Savic et al. 2004; Giovacchini et al. 2005). Serotonergic transmission was affected whether or not hippocampal atrophy or other brain structure abnormalities were present. Binding to 5-HT1A receptors in the temporal lobe was mainly decreased in areas of seizure onset and spreading (Merlet et al. 2004). However, binding may also be reduced in other forms of epilepsy such as juvenile myoclonic epilepsy (Meschaks et al. 2005). Pharmacological and post-mortem investigations have suggested changes in function and density of brain 5-HT1A receptors in patients with major depression as well (Drevets et al. 1999; Sargent et al. 2000). See Moresco et al. (2006) for a review. Binding potential of 5-HT1A receptors was reduced in frontal and temporal cortex, limbic structures and raphe nuclei (Drevets et al. 1999; Sargent et al. 2000), regardless of antidepressive treatment (Sargent et al. 2000). Similar findings were made in panic disorders with co-occurring depression (Neumeister et al. 2004). Also suicidality is associated with prefrontal impaired serotonergic metabolism (Oquendo et al. 2003). In contrast to 5-HT1A receptors, binding potential of 5-HT2 receptors in the cortex is usually increased in depression (Bhagwagar et al. 2006). This increase may be reversed by antidepressive treatment with selective serotonin re-uptake inhibitors (SSRIs; Meyer et al. 2001).

Selective serotonin re-uptake inhibitors and their impact on seizure frequency

The role of SSRIs in treatment of depression in epileptic patients has been somewhat contradictory. While some uncontrolled clinical case studies reported increased seizure frequency following SSRI administration (Hargrave et al. 1992; Prasher 1993; Tobianski and Lloyd 1995), others found no increase (Kuhn et al. 2003). In clinical practice SSRIs are therefore generally not contraindicated in epilepsy and they ameliorate depressive symptoms effectively (Thome-Souza et al. 2007). In thirty-six children and adolescents with epilepsy and depressive disorder, seizures worsened in just two patients, but all had improvement of their depression (Thome-Souza et al. 2007). Interestingly, many examiners have reported SSRI treatment to decrease evoked seizures in animals (Yan et al. 1994a,b; Browning et al. 1997; Lu and Gean 1998; Hernandez et al. 2002). In rats with TLE induced by systemic pilocarpine, seizures were reduced following fluoxetine and trifluoromethylphenylpiperazine (a non-selective 5-HT-receptor agonist; Hernandez et al. 2002). It has been suggested that a serotonergic mechanism may be involved in the anticonvulsive effect of fluoxetine in genetically epilepsy-prone rats (Yan et al. 1994a,b). In line with this, Pasini et al. reported that anticonvulsant action of fluoxetine in the substantia nigra is dependent upon endogenous 5-HT (Pasini et al. 1996).

Disturbances of serotonergic transmission

Exploration of the monoaminergic neurotransmitter systems began following observations that reserpine and similar monoamine-depleting agents can lead to depression (for review see Nutt 2006). Most antidepressants elevate synaptic levels of 5-HT and noradrenaline. This is the base for the monoamine hypothesis of depression, which postulates that depression arises from impaired monoaminergic transmission and that it is alleviated by reconstitution of normal synaptic 5-HT and noradrenaline levels (Nutt 2006). 5-HT modulates neuronal excitability in many brain areas. In hippocampus, post-synaptic 5-HT1A receptors may have either excitatory or inhibitory effects by modulating K+ conductance and membrane hyperpolarization (Colino and Halliwell 1987; Pugliese et al. 1998). As in other brain areas, serotonergic afferents to the amygdala activate both excitatory and inhibitory amino acid receptors (Rainnie et al. 1991; Mahanty and Sah 1999). Alteration of serotonergic transmission therefore changes neuronal processing in the amygdala. 5-HT probably has a net inhibitory tone on amygdala neuronal excitability (Rainnie 1999). Synaptic plasticity, including long-term potentiation and depression, has been documented in the amygdala (Keele 2005). Additionally, altered plasticity of neurotransmission is seen after epilepsy induction (Holmes et al. 1996; Neugebauer et al. 1997) and fear-conditioning (Rogan et al. 1997).

Low levels of 5-HT is the neurotransmitter deficit most clearly implicated in aggressive behavior (Popova 2006), which is often seen in mood disorders and TLE. Levels of the 5-HT metabolite 5-hydroxyindoleacetic acid in CSF are negatively correlated with aggression, hostility and lethality of suicide attempts of patients with depression (Sher et al. 2006). Low levels of 5-HT are also associated with increased aggressive and impulsive behavior in various animal models (Ferrari et al. 2005; Caramaschi et al. 2007). Diminished CSF concentrations of 5-hydroxyindoleacetic acid are related to social instability and excessive aggression in rhesus macaques (Howell et al. 2007). Mice lacking the 5-HT1B receptor show increased aggression (Ramboz et al. 1996) and impulsiveness (Brunner and Hen 1997). Consequently, agonists of 5-HT 1A and 1B receptor subtypes are effective in decreasing aggressive behavior in many animal models (Keele 2005). Similarly, antidepressants decrease impulsiveness in humans (Moeller et al. 2001) and increase the ability of rats to wait for delayed reward (Sokolowski and Seiden 1999). It can be concluded that disturbances of 5-HT metabolism with decreased CSF concentration and impaired 5-HT receptor function underlie impulsive and aggressive behavior (Ferrari et al. 2005). As mentioned earlier, anticonvulsants attenuate aggression and impulsiveness in many psychiatric disorders (Monaco et al. 2005; Stanford et al. 2005). Therefore, one may postulate that low 5-HT activity may provoke subseizure neuronal hyperexcitability in the limbic system, which possibly contributes to reduced impulse control as seen in certain emotional states such as aggression.

Noradrenaline, dopamine and their interaction with serotonergic systems

There is good evidence that noradrenaline and 5-HT interact to influence neuroplasticity in the brain (Delgado 2004). Many modern antidepressants including mirtazapine, milnacipran, venlafaxine, and duloxetine have been developed based on their interaction with both 5-HT and noradrenaline (Tran et al. 2003). The great majority of serotonergic neurons have their cell body in a tiny area in the brainstem called the raphe nuclei which belongs to the medial portion of the reticular formation; however, they send their projections through almost the entire brain. 5-HT is thought to act mainly as an inhibitory neurotransmitter. Most antidepressants are potent inhibitors of 5-HT re-uptake into the pre-synaptic neuron thereby increasing 5-HT activity in the synaptic cleft (Delgado 2004). The origin of most noradrenergic pathways in the brain is the locus ceruleus within the dorsal wall of the upper pons in the brainstem near the fourth ventricle. Like serotonergic neurons, noradrenergic neurons project bilaterally to many brain locations, including the entire cerebral cortex, limbic system, and the spinal cord (Smythies 2005). The lateral hypothalamus, the paraventricular nucleus and other areas responding to stressful stimuli have pathways synapsing with noradrenergic neurons of the locus ceruleus. These noradrenergic mechanisms may then for example mediate hypothalamo-pituitary-adrenal axis responses evoked by acute stress and arousal as explained below (Douglas 2005). Many types of antidepressants inhibit noradrenergic transporters, thereby increasing amounts of synaptic noradrenaline (Jayanthi and Ramamoorthy 2005). Few studies have so far addressed monoaminergic levels in animal models of TLE and these reports have been somewhat contradictory. In the pilocarpine model of TLE hippocampal 5-HT was increased directly after pilocarpine injection only, whereas increased levels of noradrenaline and decreased dopamine were present in the acute, latent and chronic phases (Cavalheiro et al. 1994). In contrast, other authors reported that temporal lobe seizures in pilocarpine rats did not alter amounts of dopamine and 5-HT in the hippocampus, frontal cortex and striatum (Szyndler et al. 2005). There is still much work to be done in order to clarify exactly in what ways monoaminergic concentrations are regulated by temporal lobe seizures.

During the last decade, research on pathophysiology and treatment of depression has remarkably shifted focus from the synapse and membrane receptors towards examination of intracellular signaling pathways (Coyle and Duman 2003). These pathways seem to be involved in neuroplasticity regulating diverse cognitive, emotional, autonomic and motoric functions (Coyle and Duman 2003). One of the intracellular signaling pathways mediating effects of SSRIs and other antidepressants is the cAMP cascade. cAMP is probably regulated by both 5-HT and noradrenaline (Hecimovic et al. 2003). Indeed, 5-HT and noradrenaline re-uptake inhibitors such as venlafaxine might have better effect than SSRIs because of combined action on serotonergic and noradrenergic systems. As will be explained below more in detail, it is thought that receptor activation leads via second, third and fourth messengers among others to the formation of brain derived neurotrophic factor (BDNF; Hecimovic et al. 2003). BDNF promotes neuronal plasticity and has direct antidepressant effects, underlining that – not surprisingly – antidepressive treatment involves more complex mechanisms than solely up-regulation of synaptic noradrenaline and 5-HT levels (Hecimovic et al. 2003).

Glutamatergic metabolism and glial-neuronal interactions

Glutamate and GABA

Glutamate, the most abundant excitatory neurotransmitter in the mammalian CNS (Danbolt 2001), and GABA, the most abundant inhibitory transmitter, are involved in nearly every neurological and psychiatric disorder. TLE (Chapman 2000) and depression (Kugaya and Sanacora 2005) are no exceptions. As explained above, the two disorders may share disturbed glutamate-mediated transmission in the medial temporal lobe. Synaptic glutamate homeostasis is crucial for brain function because of several reasons. First, fast removal of glutamate from the synaptic cleft guarantees short glutamate action on the post-synaptic target cell and thereby precise information signaling. Second, high extracellular concentration of glutamate is neurotoxic. Reverse transport of glutamate from glial cytosol into the extracellular space induced by energy depletion and/or release of glutamate and K+ by damaged nerve cells exacerbates brain injury (Billups and Attwell 1996). Nevertheless, vesicular release of glutamate from astrocytes in a Ca2+-dependant manner might under physiological circumstances also contribute to neuronal-astrocytic information signaling (Nedergaard et al. 2002; Liu et al. 2004; Jourdain et al. 2007). The ionotropic glutamate receptors are distinguished according to their different sensitivities to glutamate analogues: NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainate. The latter is used to induce TLE in rodents (Muller et al. 2000; Qu et al. 2003; Alvestad et al. 2007).

Glutamate is essential in epileptogenesis and during acute seizures (Chapman 2000). TLE patients have increased basal concentrations of extracellular glutamate in the epileptogenic versus non-epileptogenic hippocampus (Petroff et al. 2002a,b; Eid et al. 2004). In human mesial TLE, expression of the glutamate synthesizing enzyme phosphate-activated glutaminase is increased in hippocampal neurons, which suggests increased capacity for synthesis and disrupted homeostasis of glutamate (Eid et al. 2007). In the temporal lobe cortex and hippocampus of TLE patients, activity of glutamate dehydrogenase, the enzyme facilitating the synthesis of 2-oxoglutarate from glutamate, is decreased. Thus, on one hand more glutamate may be synthesized from glutamine, on the other hand less glutamate is probably converted to α-ketoglutarate. This decrease is correlated with the duration of intractable seizures, suggesting that impaired glutamate dehydrogenase activity may contribute to decreased metabolism and accumulation of glutamate (Malthankar-Phatak et al. 2006). Indeed, studies of TLE models (Voutsinos-Porche et al. 2006) confirm the notion that global changes to more glutamatergic and less GABAergic activities in the temporal lobes contribute significantly to epileptogenesis (El-Hassar et al. 2007). Septal GABAergic neurons, which are critical for modulation of hippocampal excitability, are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures (Garrido Sanabria et al. 2006). Probably as a compensatory mechanism, hippocampal GAD67 mRNA and expression is up-regulated in rat (Szabo et al. 2000) and human TLE (Neder et al. 2002).

Disturbances of glutamate and related metabolites are also increasingly recognized to play a role in depression and other mood disorders. Recent experimental (Stachowicz et al. 2006, 2007; Tordera et al. 2007) and clinical studies (Sanacora et al. 2007) have provided strong evidence that glutamate and other non-monoaminergic amino acids are involved in the pathophysiology of mood disorders. It seems that the exclusive monoamine theory of depression has to be abandoned (Kugaya and Sanacora 2005). 1H Magnetic Resonance Spectroscopy (MRS) studies revealed reduced glutamate concentrations in the anterior cingulate cortex in depressed adults (Auer et al. 2000) and children (Mirza et al. 2004). In a study by Hasler et al. (2007) levels of glutamate/glutamine and GABA were also decreased in prefrontal dorsomedial and ventromedial regions. Promising antidepressant effects may be achieved by modulating the glutamatergic system. Substances acting at ionotropic or G-protein-coupled second messenger activating metabotropic glutamate receptors (mGluR) ameliorated effectively depressive symptoms in preclinical and some clinical studies (for reviews see Paul and Skolnick 2003; Kugaya and Sanacora 2005; Palucha 2006). The most promising candidates include mGluR5 antagonists and group II mGluR antagonists (Stachowicz et al. 2006). Interestingly, anxiolytic effects of group III mGluR antagonists are 5-HT-dependent (Stachowicz et al. 2007), which may partly be explained by the finding that glutamatergic and GABAergic synaptic activity in the raphe nucleus appears to inhibit 5-HT receptors (Lemos et al. 2006). Moreover, several antiepileptics inhibiting glutamatergic transmission have well-known antidepressant properties (Kugaya and Sanacora 2005). Riluzole, a NMDA glutamate antagonist used to treat amyotrophic lateral sclerosis, increases antidepressive effects when added to conventional treatment (Sanacora et al. 2007), possibly because of the fact that NMDA receptor antagonists block fear processing and conditioning in the amygdala (Davis 2006; Garakani et al. 2006). In addition, the anxiolytic effects of benzodiazepines due to increased GABAA activity are well-known. Although much research still needs to be done, the cited and many other studies on the glutamatergic system provide robust data that challenge the hypothesis of depression as a result of exclusive monoaminergic disturbances.

Glial-neuronal interactions

Glial and neuronal metabolism is intimately connected. In contrast to neurons, astrocytes can have net synthesis of glutamate as they are able to convert pyruvate to oxaloacetate via the brain’s main anaplerotic enzyme, pyruvate carboxylase (Shank et al. 1985). Net synthesis of neuronal tricarboxylic acid cycle metabolites and compounds like glutamate and GABA require the entry of a four-carbon unit. Pyruvate carboxylase in astrocytes therefore transforms pyruvate to oxaloacetate resulting after condensation with acetyl CoA in the formation of the TCA cycle intermediate citrate, which can be further converted to α-ketoglutarate. From the latter, glutamate can be formed via glutamate dehydrogenase or different transaminases, but more importantly, in neurons glutamate can emerge from glutamine after hydrolysis by phosphate-activated glutaminase. The latter pathway is part of the so-called ‘glutamine-glutamate cycle’ (Hertz 1979). Shortly, astrocytes release glutamine into the extracellular space, from where it is taken up by neurons, converted to glutamate and further, in GABAergic cells, to GABA. After release upon depolarization, glutamate is cleared from the synaptic cleft by astrocytes and converted to glutamine, which closes the cycle. Note that GABA is predominately taken up into neurons (Schousboe 2003). The significance of astrocytic clearing of glutamate as part of the ‘glutamine-glutamine-cycle’ is illustrated by the fact that glutamate/aspartate transporter and glutamate transporter which account for most of the glutamate transport, are primarily found on astroglial cells (Danbolt 2001).

As astrocytes are so intimately connected to glutamate metabolism, it seems necessary to assume that they play a major role in epilepsy and depression. Indeed, titles of recent reviews such as ‘Astrocytes have a key role in epilepsy’ (Siva 2005), ‘Astrocytes get in the act in epilepsy’ (Rogawski 2005), and ‘Gliogenesis and glial pathology in depression’ (Rajkowska and Miguel-Hidalgo 2007) corroborate this notion. Astrocytic activation and gliosis, together with neuronal loss, are the most significant histological features of hippocampal sclerosis seen in mesial TLE (Binder and Steinhauser 2006). Moreover, as astrocytic modulation of synaptic transmission between neurons is now well-recognized (Verkhratsky and Toescu 2006), an increase in glial cell number or volume may contribute to hyperexcitability of hippocampal neurons in epilepsy and a decrease to hypoexcitability of the frontal cortex in depression. Indeed, decreased amounts of glutamate, glutamine and GABA have been reported in the frontal lobe of patients with major depression (Hasler et al. 2007) in addition to a decrease in number of astrocytes (Ongur et al. 1998). This implies disturbed glial-neuronal interactions in the frontal lobe during depression, which also have been reported for this and other areas in experimental TLE (Binder and Steinhauser 2006; Melo et al. 2006). Changes in astrocyte membrane channels, receptors and transporters have all been associated with epileptogenesis and seizures (for a review, see Binder and Steinhauser 2006). As both extracellular K+ concentration and osmolarity have great impact on neural excitability, it is likely that alterations of astrocytic K+ and aquaporine water channels, detected in TLE specimens (Eid et al. 2005), contribute to epileptic hyperexcitability. Simple transitory opening of the blood-brain-barrier, which are covered by astrocytic end-feet, can under certain circumstances be sufficient for focal epileptogenesis (Seiffert et al. 2004). Newly generated glial cells can migrate into the hippocampus and contribute to enhanced seizure susceptibility (Parent et al. 2006). In some models of epilepsy, blockade of neuronal death in the hippocampus may prevent limbic brain damage, but not epileptogenesis (Halonen et al. 2001; Brandt et al. 2003). This implies that neurodegeneration alone may not lead to epilepsy. In a study by Kang et al. on pilocarpine-induced status epilepticus, microgliosis and astroglial death occurred first and preceded neuronal damage, abnormal neurotransmission of glutamate and GABA, and mossy fiber sprouting in the dentate gyrus. In addition, expressions of glutamine synthetase, glutamate dehydrogenase, and GABA transporters were down-regulated in newly generated astrocytes (Kang et al. 2006). Thus, glial reactions to status epilepticus probably add to epileptogenesis and hyperexcitability of temporal lobe structures. As astrocytes take up the great bulk of synaptic glutamate (Danbolt 2001), it is reasonable to assume that impaired glial glutamate metabolism and astrocytic-neuronal interactions play the greatest part in neurotransmitter disturbances in epilepsy and depression. In mesial temporal sclerosis down-regulation of glutamine synthetase causes a diminuation of the glutamate-glutamine cycling and accumulation of the transmitter in astrocytes and in the extracellular space (Eid et al. 2004). This has been confirmed by 1H and 13C MRS in resected human epileptic hippocampus after injection of [2-13C]glucose (Petroff et al. 2002a,b). Petroff et al. concluded that hippocampal sclerosis seems to be characterized by slow rates of glutamate-glutamine cycling, decreased glutamine content, and a relative increase of glutamate levels. The authors suggested that the low rate of glutamate-glutamine cycling may result from a failure of glial glutamate detoxification because of slow clearance from synapses and continuing excitotoxicity (Petroff et al. 2002a,b). However, in animals 13C MRS may be used to study metabolism specific to neurons and astrocytes (Sonnewald and Kondziella 2003). When [1-13C]glucose and [1,2-13C]acetate are given simultaneously, glial-neuronal interactions can be studied in the same animal because of the fact that [1,2-13C]acetate is exclusively taken-up by astrocytes, whereas most of the acetyl-CoA derived from [1-13C]glucose is metabolized in neurons (Sonnewald and Kondziella 2003). In animal studies of TLE using 13C MRS increased astrocytic activity in rats 1 day after status epilepticus (Qu et al. 2003) resulted after 2 weeks of epileptogenesis in an increased amino acid turnover in neurons (Muller et al. 2000). Chronic TLE 2 months after status epilepticus then again lead to decreased neuronal metabolism in the rat hippocampal formation with lowered glutamate levels (Melo et al. 2006; Alvestad et al. 2007). Epileptic kindling with pentylenetetrazole, a convulsant decreasing GABA activity, alters mainly metabolism of astrocytes in young and of glutamatergic neurons in old mice (Kondziella et al. 2002, 2003).

Of particular importance is the novel observation that astrocytes show Ca2+-induced release of glutamate, which directly excites surrounding neurons (Volterra and Meldolesi 2005). Thus, not only is glutamate-uptake of astrocytes in epilepsy reduced, but astrocytes are also capable of releasing glutamate through a Ca2+-dependent process, which might be involved in seizure generation (Kang et al. 2005; D’Ambrosio 2006). In a study of acute epilepsy models, Tian et al. (2005) reported that astrocytes can initiate synchronized epileptiform activity because of paroxysmal depolarizing shifts induced by glutamate release. This may indeed be an ‘astrocytic basis for epilepsy’ (Tian et al. 2005). Should further studies confirm the finding, this pathway may present a promising novel therapeutic target.

Hypothalamus-pituitary-adrenal axis, glucocorticoids and the contradictory effects of brain-derived neurotrophic factor

In depression and other psychiatric disorders, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and neurotoxicity because of elevated levels of glucocorticoids are well-described (Carroll et al. 2007). Briefly, corticotropin-releasing factor (CRF) is secreted by the hypothalamus, which stimulates synthesis and release of adrenocorticotropin (ACTH) from the pituitary gland. ACTH then promotes secretion of glucocorticoids from the adrenal cortex. Glucocorticoid levels are highly regulated by feedback mechanisms. Several brain structures control activity of the HPA axis, including the amygdala having excitatory influence, and the hippocampus having inhibitory influence on hypothalamic CRF-containing neurons (Nestler et al. 2002). Elevation of glucocorticoids during depression and chronic stress leads to injury of synapses (Mason and Pariante 2006; Tata et al. 2006), particularly involving CA3 pyramidal neurons, reduction of dendritic branching and spines (Sapolsky 2000), and ultimately to neuronal cell loss and atrophy of the hippocampus (Jacobsen and Mork 2006). Glutamate excitotoxicty probably has a role in these mechanisms (Lee et al. 2002). Further, hypercortisolemia possibly hampers the development of new granule cell neurons in the hippocampal dentate gyrus (Hecimovic et al. 2003). It has been suggested that both serotonergic (Leonard 2005) and noradrenergic systems (Cameron 2006) interact with the HPA axis. Indeed, excessive activation of the HPA axis is reversed by SSRIs and other antidepressants (Miller and O’Callaghan 2005; Mason and Pariante 2006). Antiglucocorticoids such as steroid synthesis inhibitors and antagonists of CRF and glucocorticoid receptors have shown promising antidepressive effects in both preclinical and clinical studies (Young 2006). However, there is still controversy whether abnormalities of the HPA axis primarily provoke depression or merely are part of secondary mechanisms.

Increased glucocorticoid concentrations during depression and chronic stress are also associated with a decrease of neurotrophic factors such as BDNF (Duman and Monteggia 2006). As mentioned earlier, during the last decade research on depression has shifted focus from neurotransmitter levels and synaptic receptors towards intracellular signaling pathways (Coyle and Duman 2003). One of the better-known intracellular pathways mediating effects of antidepressant drugs is the cAMP cascade, which apparently is influenced by both 5-HT and noradrenaline (Hecimovic et al. 2003). Activation of neurotransmitter receptors generates cAMP and as a consequence, cAMP-dependent protein kinase is activated (Coyle and Duman 2003). A substrate of protein kinase is the transcription factor cAMP response element-binding protein, which mediates expression of BDNF. Neurotrophic factors are important in plasticity and survival of adult neurons and glia (Duman 2004). A deficiency in neurotrophic support by BDNF contributes to hippocampal pathology. Reversal of this deficiency during antidepressant treatment is believed to alleviate depressive symptoms. Long-term administration of antidepressant drugs increases BDNF expression in several brain regions, including the hippocampus (Chen et al. 2001; Conti et al. 2004; Tardito et al. 2006), and prevents stress-induced decrease in BDNF levels (Russo-Neustadt and Chen 2005; Duman and Monteggia 2006). A single bilateral infusion of BDNF into the rat hippocampus or the midbrain produces antidepressant effects comparable in size to repeated administration of antidepressant drugs (Siuciak et al. 1997; Shirayama et al. 2002). However, the outlined mechanisms of intracellular signaling are most likely present not only in animals, but also in humans (Chen et al. 2001; Russo-Neustadt and Chen 2005).

As the hippocampus has critical implications for both seizure activity and mood disorders, this area provides a link between epilepsy and depression (Hajszan and MacLusky 2006). Not surprisingly, dysregulation of the HPA axis (Zobel et al. 2004) and BDNF (Scharfman 2005) have therefore been suggested to play a role in the development of TLE. However, this role has been somewhat contradictory. Patients with TLE have indeed enhanced secretion of ACTH, independent of AEDs or seizure frequency, and secretion normalizes after temporal lobe resection (Gallagher 1987). Cortisol levels rise in serum after temporal lobe seizures, but may do so even after other epileptic seizures (Takeshita et al. 1986; Pritchard 1991). Although excessive activation of the HPA axis has been confirmed in TLE (Zobel et al. 2004), this is also true for non-TLE (Zobel et al. 2004), Alzheimer’s disease (Rasmuson et al. 2001) and multiple sclerosis (Then Bergh et al. 2001). Thus, HPA axis derangement is far from being specific for TLE. It may, however, predispose epileptic patients to subsequent development of depression. Whether this association is bidirectional remains to be determined.

The role of BDNF seems even less clear, as in TLE BDNF may have both positive effects, because of neuroprotection, and deleterious effects, possibly because of stimulation of aberrant neuronal circuits (Scharfman 2005). On one hand, BDNF is up-regulated in the hippocampus and other brain areas during epileptogenesis in humans (Mathern et al. 1997; Murray et al. 2000). Patch-clamp recordings from dentate granule cells in hippocampal slices have confirmed that BDNF elicits hyperexcitability in non-epileptic rat brain (Asztely et al. 2000; Koyama et al. 2004) and in human TLE (Zhu and Roper 2001). In support of these findings, blocking of BDNF prevents hyperactivity-induced mossy fiber sprouting (Koyama et al. 2004). On the other hand, several reports demonstrate that prolonged intrahippocampal infusion of BDNF can ameliorate or prevent TLE in rats (Larmet et al. 1995; Osehobo et al. 1999; Reibel et al. 2000a,b). The antiepileptogenic effect of BDNF is apparently mediated by increased activity of neuropeptide Y and perhaps also by potentiation of GABAergic inhibition (Koyama and Ikegaya 2005). It can be concluded that in contrast to what one might expect BDNF function seems to be down-regulated in depression and up-regulated in TLE. To our knowledge, there are yet no explicit data on BDNF in patients suffering from simultaneous TLE and depression. A single intrahippocampal infusion of BDNF has antidepressive effects in animal models (Siuciak et al. 1997; Shirayama et al. 2002), but may occasionally provoke seizures (Scharfman et al. 2002). However, as mentioned above, repeated BDNF infusions have antiepileptogenic effects (Larmet et al. 1995; Osehobo et al. 1999; Reibel et al. 2000a,b). Thus, BDNF function appears to be time-dependant. At least theoretically, up-regulation in chronic TLE might be a compensatory mechanism in so far as the benefits from BDNF-induced survival of hippocampal neurons may outweigh the deleterious effects from aberrant neuronal circuits. However, to clarify the ambiguous observations on BDNF in depression and TLE, it seems necessary to further evaluate by what means precisely BDNF influences neuronal networks.

A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging

  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References

Because of delicate in vivo and ex vivo techniques such as PET, MRI and MRS, we have witnessed how a complex pattern of common pathogenic mechanisms of TLE and depression becomes apparent. Data linking the two disorders stem from molecular, cellular and regional levels in the brain (Fig. 1). Monoaminergic neurotransmitters such as 5-HT and noradrenaline interact with glutamatergic metabolites, which may lead to disturbances of neuronal circuits. Neuronal hyperexcitability can possibly be expressed either as impaired emotions or seizure activity. In addition, reduced synaptic levels of neurotransmitters and high levels of glucocorticoids may cause disturbances of neurotrophic factors via cAMP and other intracellular signaling pathways. Atrophy of hippocampus and memory impairment develops, as do transient hypertrophy of amygdala and impaired fear processing. Glucose metabolism may be down-regulated in both frontal and temporal lobes. Moreover, astrocytes seem to have an intriguing role reaching far beyond the formation of scar tissue in hippocampal sclerosis. All these mechanisms are probably bidirectional. The structural and functional alterations from one disease may evoke the other and vice versa. Although the initial pathologic event from either depression or TLE can vary in its noxious effects, repeated episodes may have a kindling effect leading to the subsequent co-occurrence of the other disease. In TLE, for instance, hyperexcitability and neuronal cell loss in the limbic system may evoke mood disturbances, whereas hippocampal atrophy and neurotransmitter disturbances in depression may decrease the seizure threshold and ultimately lead to TLE. In a given subject suffering from combined TLE and depression, however, these pathophysiological mechanisms are obviously strongly intertwined and cannot be attributed strictly to one or the other of the two diseases. In a recent editorial, A.M. Kanner (2006a) wrote: ‘The million-dollar question is whether timely treatment of the depressive disorder lowers the risk of developing an unprovoked epileptic seizure or an epileptic seizure disorder.’ To answer this, future studies have to address in what ways SSRIs and other antidepressive drugs have impact on epileptogenesis. Do SSRIs have neuroprotective effects in the temporal lobe of TLE rats? What precisely are the mechanisms by which antiepileptics modify mood disturbances? Might specific modulation of glial receptors prevent reactive gliosis, improve glial-neuronal interactions and have antidepressive and antiepileptic properties? Exciting new studies are to be expected in the near future.


  1. Top of page
  2. Abstract
  3. Introductory remarks on human temporal lobe epilepsy and depression
  4. Animal behavior in models of temporal lobe epilepsy and depression
  5. Brain metabolism, transmitters, neuronal circuits and glial-neuronal interactions
  6. A pattern of common mechanisms in temporal lobe epilepsy and depression is emerging
  7. References
  • Adamec R. and McKay D. (1993) Amygdala-kindling, anxiety, and corticotrophin releasing factor (crf.). Physiol. Behav. 53, 531545.
  • Adamec R. and Morgan H. D. (1994) The effect of kindling of different nuclei in the left and right amygdala on anxiety in the rat. Physiol. Behav. 55, 112.
  • Adamec R. and Young B. (2000) Neuroplasticity in specific limbic system circuits may mediate specific kindling induced changes in animal affect: implications for understanding anxiety associated with epilepsy. Neurosci. Biobehav. Rev. 24, 705723.
  • Alonso N. B., Ciconelli R. M., Da Silva T. I., Westphal-Guitti A. C., Azevedo A. M., Da Silva Noffs M. H., Caboclo L. O., Sakamoto A. C. and Targas Yacubian E. M. (2006) The Portuguese version of the Epilepsy Surgery Inventory (ESI-55): cross-cultural adaptation and evaluation of psychometric properties. Epilepsy Behav. 9, 126132.
  • Altshuler L., Rausch R., Delrahim S., Kay J. and Crandall P. (1999) Temporal lobe epilepsy, temporal lobectomy, and major depression. J. Neuropsychiatry Clin. Neurosci. 11, 436443.
  • Alvestad S., Hammer J., Eyjolfsson E., Qu H., Ottersen O. P. and Sonnewald U. (2007) Limbic structures show altered glial-neuronal metabolism in the chronic phase of kainate induced epilepsy. Neurochem. Res. (in press)
  • Asztely F.., Kokaia M., Olofsdotter K., Ortegren U. and Lindvall O. (2000) Afferent-specific modulation of short-term synaptic plasticity by neurotrophins in dentate gyrus. Eur. J. Neurosci. 12, 662669.
  • Asztely F., Ekstedt G., Rydenhag B. and Malmgren K. (2007) Long-term follow-up of the first 70 operated adults in the Goteborg epilepsy surgery series with respect to seizures, psychosocial outcome and use of anti-epileptic drugs. J. Neurol. Neurosurg. Psychiatry [Epub ahead of print].
  • Auer D. P., Putz B., Kraft E., Lipinski B., Schill J. and Holsboer F. (2000) Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol. Psychiatry 47, 305313.
  • Baker G. A. (2006) Depression and suicide in adolescents with epilepsy. Neurology 66, S5S12.
  • Baxendale S., Thompson P. J. and Duncan J. S. (2005) Epilepsy & depression: the effects of comorbidity on hippocampal volume – a pilot study. Seizure 14, 435438.
  • Beneyto M., Kristiansen L. V., Oni-Orisan A., McCullumsmith R. E. and Meador-Woodruff J. H. (2007) Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology [Epub ahead of print].
  • Ben-Menachem E. (2001) Vagus nerve stimulation, side effects, and long-term safety. J. Clin. Neurophysiol. 18, 415418.
  • Bhagwagar Z., Hinz R., Taylor M., Fancy S., Cowen P. and Grasby P. (2006) Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. Am. J. Psychiatry 163, 15801587.
  • Billups B. and Attwell D. (1996) Modulation of non-vesicular glutamate release by pH. Nature 379, 171174.
  • Binder D. K. and Steinhauser C. (2006) Functional changes in astroglial cells in epilepsy. Glia 54, 358368.
  • Blumer D., Montouris G. and Hermann B. (1995) Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J. Neuropsych. Clin. Neurosci. 7, 445456.
  • Blumer D., Montouris G. and Davies K. (2004) The interictal dysphoric disorder: recognition, pathogenesis, and treatment of the major psychiatric disorder of epilepsy. Epilepsy Behav. 5, 826840.
  • Boylan L. S., Flint L. A., Labovitz D. L., Jackson S. C., Starner K. and Devinsky O. (2004) Depression but not seizure frequency predicts quality of life in treatment resistant epilepsy. Neurology 62, 258261.
  • Brandt C., Potschka H., Loscher W. and Ebert U. (2003) N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainite model of temporal lobe epilepsy. Neuroscience 118, 727740.
  • Bremner J. D., Narayan M., Anderson E. R., Staib L. H., Miller H. L. and Charney D. S. (2000) Hippocampal volume reduction in major depression. Am. J. Psychiatry 152, 973981.
  • Bromfield E. B., Altshuler L. and Leiderman D. B. (1992) Cerebral metabolism and depression in patients with complex partial seizures. Arch. Neurol. 49, 617623.
  • Browning R. A., Wood A. V., Merrill M. A., Dailey J. W. and Jobe P. C. (1997) Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT1A receptors. Eur. J. Pharmacol. 336, 16.
  • Bruchey A. K., Shumake J. and Gonzalez-Lima F. (2006) Network model of fear extinction and renewal functional pathways. Neuroscience [Epub ahead of print].
  • Brunner D. and Hen R. (1997) Insights into the neurobiology of impulsive behavior from serotonin receptor knockout mice. Ann. NY Acad. Sci. 836, 81105.
  • Cameron O. G. (2006) Anxious-depressive comorbidity: effects on HPA axis and CNS noradrenergic functions. Essent. Psychopharmacol. 7, 2434.
  • Cammisuli S., Murphy M. P., Ikeda-Douglas C. J., Balkissoon V., Holsinger R. M., Head E., Michael M., Racine R. J. and Milgram N. W. (1997) Effects of extended electrical kindling on exploratory behavior and spatial learning. Behav. Brain Res. 89, 179190.
  • Caramaschi D., De Boer S. F. and Koolhaas J. M. (2007) Differential role of the 5-HT(1A) receptor in aggressive and non-aggressive mice: an across-strain comparison. Physiol. Behav. [Epub ahead of print].
  • Carroll B. J, Cassidy F., Naftolowitz D., Tatham N. E., Wilson W. H., Iranmanesh A., Liu P. Y. and Veldhuis J. D. (2007) Pathophysiology of hypercortisolism in depression. Acta Psychiatr. Scand. 433, S90S103.
  • Casse R., Rowe C. C., Newton M., Berlangieri S. U. and Scott A. M. (2002) Positron emission tomography and epilepsy. Mol. Imaging Biol. 4, 338351.
  • Cavalheiro E. A., Fernandes M. J., Turski L. and Naffah-Mazzacoratti M. G. (1994) Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus. Epilepsia 35, 111.
  • Cavazos J. E. and Cross D. J. (2006) The role of synaptic reorganization in mesial temporal lobe epilepsy. Epilepsy Behav. 83, 483493.
  • Cendes F., Cook M. J., Watson C., Andermann F., Fish D. R., Shorvon S. D., Bergin P., Free S., Dubeau F. and Arnold D. L. (1995) Frequency and characteristics of dual pathology in patients with lesional epilepsy. Neurology 45, 20582064.
  • Chapman A. G. (2000) Glutamate and epilepsy. J. Nutr. 130, S1043S1045.
  • Chen B., Dowlatshahi D., MacQueen G. M., Wang J. F. and Young L. T. (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol. Psychiatry 50, 260265.
  • Choi J. Y., Kim S. J., Hong S. B., Seo D. W., Hong S. C., Kim B. T. and Kim S. E. (2003) Extratemporal hypometabolism on FDG PET in temporal lobe epilepsy as a predictor of seizure outcome after temporal lobectomy. Eur. J. Nucl. Med. Mol. Imaging 304, 581587.
  • Colino A. and Halliwell J. V. (1987) Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin. Nature 328, 7377.
  • Conti F., Minelli A. and Melone M. (2004) GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res. Brain Res. Rev. 45, 196212.
  • Coulter D., McIntyre D. and Loscher W. (2002) Animal models of limbic epilepsies: what can they tell us? Brain Pathol. 12, 240256.
  • Coyle J. T. and Duman R. S. (2003) Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157160.
  • D’Ambrosio R. (2006) Does glutamate released by astrocytes cause focal epilepsy? Epilepsy Curr. 6, 173176.
  • D’Mello G. D. and Steckler T. (1996) Animal models in cognitive behavioural pharmacology: an overview. Brain Res. Cogn. Brain Res. 3, 345352.
  • Danbolt N. C. (2001) Glutamate uptake. Progress Neurobiol. 65, 1105.
  • Davis M. (2006) Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am. Psychol. 61, 741756.
  • Delgado P. L. (2004) Common pathways of depression and pain. J. Clin. Psychiatry 65, S16S19.
  • Depaulis A., Helfer V., Deransart C. and Marescaux C. H. (1997) Anxiogenic-like consequences in animal models of complex partial seizures. Neurosci. Behav. Rev. 6, 767774.
  • Detour J., Schroeder H., Desor D. and Nehlig A. (2005) A 5-month period of epilepsy impairs spatial memory, decreases anxiety, but spares object recognition in the lithium-pilocarpine model in adult rats. Epilepsia 46, 499508.
  • Devinsky O., Barr W. B., Vickrey B. G. et al. (2005) Changes in depression and anxiety after resective surgery for epilepsy. Neurology 65, 17441749.
  • Dos Santos Jr J. G., Longo B. M., Blanco M. M., Menezes de Oliveira M. G. and Mello L. E. (2005) Behavioral changes resulting from the administration of cycloheximide in the pilocarpine model of epilepsy. Brain Res. 1066, 3748.
  • Douglas A. J. (2005) Central noradrenergic mechanisms underlying acute stress responses of the hypothalamo-pituitary-adrenal axis: adaptations through pregnancy and lactation. Stress 8, 518.
  • Drevets W. C. (2000) Neuroimaging studies of mood disorders. Biol. Psychiatry 48, 813829.
  • Drevets W. C., Frank E., Price J. C., Kupfer D. J., Holt D., Greer P. J., Huang Y., Gautier C. and Mathis C. (1999) PET imaging of serotonin 1A receptor binding in depression. Biol. Psychiatry 46, 13751387.
  • Dulay M. F., Schefft B. K., Fargo J. D., Privitera M. D. and Yeh H. S. (2004) Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy. Epilepsy Behav. 5, 522531.
  • Duman R. S. (2004) Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromol. Med. 5, 1125.
  • Duman R. S. and Monteggia L. M. (2006) A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 11161127.
  • Eid T., Thomas M. J., Spencer D. D., Runden-Pran E., Lai J. C., Malthankar G. V., Kim J. H., Danbolt N. C., Ottersen O. P. and De Lanerolle N. C. (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 2837.
  • Eid T., Lee T. S., Thomas M. J., Amiry-Moghaddem M., Bjornsen L. P., Spencer D. D., Agre P., Ottersen O. P. and De Lanerolle N. C. (2005) Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostatis in the human epileptogenic hippocampus. Proc. Natl. Acad. Sci. USA 102, 11931198.
  • Eid T., Hammer J., Runden-Pran E. et al. (2007) Increased expression of phosphate-activated glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy. Acta Neuropathol. 113, 137152.
  • El-Hassar L., Milh M., Wendling F., Ferrand N., Esclapez M. and Bernard C. (2007) Cell domain-dependent changes in the glutamatergic and GABAergic drives during epileptogenesis in the rat CA1 region. J. Physiol. 578, 193211.
  • Ferrari P. F., Palanza P., Parmigiani S., De Almeida R. M. and Miczek K. A. (2005) Serotonin and aggressive behavior in rodents and nonhuman primates: predispositions and plasticity. Eur. J. Pharmacol. 526, 259273.
  • Forsgren L. and Nystrom L. (1999) An incident case referent study of epileptic seizures in adults. Epilepsy Res. 6, 6681.
  • Frodl T., Meisenzahl E., Zetsche T., Rottlender R., Born C., Groll C., Jäger M., Leinsinger G., Hahn K. and Möller H. J. (2002) Enlargement of the amygdala in patients with a first episode of major depression. Biol. Psychiatry 51, 708714.
  • Gajwani P., Forsthoff A., Muzina D., Amann B., Gao K., Elhaj O., Calabrese J. R. and Grunze H. (2005) Antiepileptic drugs in mood-disordered patients. Epilepsia 46, S38S44.
  • Gallagher B. B. (1987) Endocrine abnormalities in human temporal lobe epilepsy. Yale J. Biol. Med. 60, 9397.
  • Garakani A., Mathew S. J. and Charney D. S. (2006) Neurobiology of anxiety disorders and implications for treatment. Mt Sinai J. Med. 73, 941949.
  • Garrido Sanabria E. R., Castaneda M. T., Banuelos C., Perez-Cordova M. G., Hernandez S. and Colom L. V. (2006) Septal GABAergic neurons are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures. Neuroscience 142, 871883.
  • Gascino G. D., Jack Jr C. R., Parisi J. E., Sharbrough F. W., Hirschhorn K. A., Meyer F. B., Marsh W. R. and O’Brien P. C. (1991) Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations. Ann. Neurol. 30, 3136.
  • Gilliam F., Hecimovic H. and Sheline Y. (2003) Psychiatric comorbidity, health, and function in epilepsy. Epilepsy Behav. 4, S26S30.
  • Giovacchini G., Toczek M. T., Bonwetsch R. et al. (2005) 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J. Nucl. Med. 46, 11281135.
  • Hajszan T. and MacLusky N. J. (2006) Neurologic links between epilepsy and depression in women: is hippocampal neuroplasticity the key? Neurology 66, S13S22.
  • Halonen T., Nissinen J. and Pitkanen A. (2001) Chronic elevation of brain GABA levels beginning two days after status epilepticus does not prevent epileptogenesis in rats. Neuropharmacol. 40, 536550.
  • Harden C. L. (2002) The co-morbidity of depression and epilepsy. Neurology 59, S48S55.
  • Harden C. L. and Goldstein M. A. (2002) Mood disorders in patients with epilepsy: epidemiology and treatment. CNS Drugs 16, 291302.
  • Hargrave R., Martinez D. and Bernstein A. J. (1992) Fluoxetine-induced seizures. Psychosomatics 33, 236239.
  • Hasler G., Van Der Veen J. W., Tumonis T., Meyers N., Shen J. and Drevets W. C. (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 64, 193200.
  • Hecimovic H., Goldstein J. D., Sheline Y. I. and Gilliam F. G. (2003) Mechanisms of depression in epilepsy from a clinical perspective. Epilepsy Behav. 4, S25S30.
  • Helfer V., Deransart C., Marescaux C. and Depaulis A. (1996) Amygdala kindling in the rat: anxiogenic-like consequences. Neuroscience 73, 971978.
  • Helmstaedter C., Sonntag-Dillender M., Hoppe C. and Elger C. E. (2004) Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization. Epilepsy Behav. 5, 696701.
  • Henke P. G. and Sullivan R. M. (1985) Kindling in the amygdala and susceptibility to stress ulcers. Brain Res. Bull. 400, 360364.
  • Henry T. R. and Votaw J. R. (2004) The role of positron emission tomography with [18F]fluorodeoxyglucose in the evaluation of the epilepsies. Neuroimaging Clin. N. Am. 14, 517535.
  • Hermann B., Seidenberg M. and Bell B. (2000) Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression. Epilepsia 41, S31S41.
  • Hernandez E. J., Wiliams P. A. and Dudek F. E. (2002) Effects of fluoxetine and TFMPP on spontaneous seizures in rats with pilocarpine-induced epilepsy. Epilepsia 43, 13371345.
  • Hertz L. (1979) Functional interactions between neurons and astrocytes. I. Turnover and metabolism of putative amino acid transmitters. Prog. Neurobiol. 13, 277323.
  • Hesdorffer D. C., Hauser W. A., Annegers J. F. and Gascino G. (2000) Major depression is a risk factor for seizures in older adults. Ann. Neurol. 47, 246249.
  • Hesdorffer D. C., Hauser W. A., Olafsson E., Ludvigsson P. and Kjartansson D. (2006) Depression and suicide attempt as risk factors for incident unprovoked seizures. Ann. Neurol. 59, 3541.
  • Ho S. S., Consalvo D., Gilliam F., Faught E., Bilir E., Morawetz R. and Kuzniecky R. I. (1998) Amygdala atrophy and seizure outcome after temporal lobe epilepsy surgery. Neurology 5, 15021504.
  • Holmes K. H., Keele N. B., Arvanov V. L. and Shinnick-Gallagher P. (1996) Metabotropic glutamate receptor agonist-induced hyperpolarizations in rat basolateral amygdala neurons: receptor characterization and ion channels. J. Neurophysiol. 76, 30593069.
  • Hort J., Brozek G., Mares P., Langmeier M. and Komarek V. (1999) Cognitive functions after pilocarpine-induced status epilepticus: changes during silent period precede appearance of spontaneous recurrent seizures. Epilepsia 40, 11771183.
  • Howell S., Westergaard G., Hoos B., Chavanne T. J., Shoaf S. E., Cleveland A., Snoy P. J., Suomi S. J. and Dee Higley J. (2007) Serotonergic influences on life-history outcomes in free-ranging male rhesus macaques. Am. J. Primatol. [Epub ahead of print].
  • Hughes C. R. and Keele N. B. (2006) Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats. Epilepsy Behav. 9, 557563.
  • Jacobsen J. P. and Mork A. (2006) Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat. Brain Res. 1110, 221225.
  • Jayanthi L. D. and Ramamoorthy S. (2005) Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. AAPS J. 7, 728738.
  • Joo E. Y., Lee E. K., Tae W. S. and Hong S. B. (2004) Unitemporal vs bitemporal hypometabolism in mesial temporal lobe epilepsy. Arch. Neurol. 61, 10741078.
  • Jourdain P., Bergersen L. H., Bhaukaurally K., Bezzi P., Santello M., Domercq M., Matute C., Tonello F., Gundersen V. and Volterra A. (2007) Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331339.
  • Kalynchuk L. E. (2000) Long-term kindling in rats as a model for the study of interictal emotionality in temporal lobe epilepsy. Neurosci. Behav. Rev. 24, 691704.
  • Kalynchuk L. E., Pinel J. P. and Treit D. (1998) Long-term kindling and interictal emotionality in rats: effect of stimulation site. Brain Res. 779, 149157.
  • Kang N., Xu J., Xu Q., Nedergaard M. and Kang J. (2005) Astrocytic glutamate release–induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 94, 41214130.
  • Kang T. C., Kim D. S., Kwak S. E., Kim J. E., Won M. H., Kim D. W., Choi S. Y. and Kwon O. S. (2006) Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy. Glia 54, 258271.
  • Kann O., Kovacs R., Njunting M., Behrens C. J., Otahal J., Lehmann T. N., Gabriel S. and Heinemann U. (2005) Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans. Brain 128, 23962407.
  • Kanner A. M. (2003) Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol. Psychiatry 54, 388398.
  • Kanner A. M. (2006a) Epilepsy, suicidal behaviour, and depression: do they share common pathogenic mechanisms? Lancet Neurol. 5, 107108.
  • Kanner A. M. (2006b) Depression and epilepsy: a new perspective on two closely related disorders. Epilepsy Curr. 6, 141146.
  • Kanner A. M. and Balabanov A. (2002) Depression and epilepsy: how closely related are they? Neurology 58, S27S39.
  • Keele N. B. (2001) Phenytoin inhibits isolation-induced aggression specifically in rats with low serotonin. Neuroreport 12, 110712.
  • Keele N. B. (2005) The role of serotonin in impulsive and aggressive behaviors associated with epilepsy-like neuronal hyperexcitability in the amygdala. Epilepsy Behav. 7, 325335.
  • Kim M. A., Heo K., Choo M. K., Cho J. H., Park S. C., Lee J. D., Yun M., Park H. J. and Lee B. I. (2006) Relationship between bilateral temporal hypometabolism and EEG findings for mesial temporal lobe epilepsy: analysis of 18F-FDG PET using SPM. Seizure 15, 5663.
  • Kondziella D., Bidar A., Urfjell B., Sletvold O. and Sonnewald U. (2002) The pentylenetetrazole-kindling model of epilepsy in SAMP8 mice: behavior and metabolism. Neurochem. Int. 40, 413418.
  • Kondziella D., Hammer J., Sletvold O. and Sonnewald U. (2003) The pentylenetetrazole-kindling model of epilepsy in SAMP8 mice: glial-neuronal metabolic interactions. Neurochem. Int. 43, 629637.
  • Koyama R. and Ikegaya Y. (2005) To BDNF or not to BDNF: that is the epileptic hippocampus. Neuroscientist 11, 282287.
  • Koyama R., Yamada M. K., Fujisawa S., Katoh-Semba R., Matsuki N. and Ikegaya Y. (2004) Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus. J. Neurosci. 24, 72157224.
  • Kugaya A. and Sanacora G. (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 10, 808819.
  • Kuhn K. U., Quednow B. B., Thiel M., Falkai P., Maier W. and Elgerb C. E. (2003) Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressant. Epilepsy Behav. 4, 674679.
  • Kunz W. S., Kudin A. P., Vielhaber S., Blumcke I., Zuschratter W., Schramm J., Beck H. and Elger C. E. (2000) Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy. Ann. Neurol. 48, 766773.
  • Kuzniecky R., Ho S. S., Martin R., Faught E., Morawetz R., Palmer C. and Gilliam F. (1999) Temporal lobe developmental malformations and hippocampal sclerosis: epilepsy surgical outcome. Neurology 52, 479484.
  • Labiner D. M. and Ahern G. L. (2007) Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings. Acta Neurol. Scand. 115, 2333.
  • Larmet Y., Reibel S., Carnahan J., Nawa H., Marescaux C. and Depaulis A. (1995) Protective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat. Neuroreport 6, 19371941.
  • Lavretsky H., Ballmaier M., Pham D., Toga A. and Kumar A. (2007) Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study. Am. J. Geriatr. Psychiatry 15, 386394.
  • Lee A. L., Ogle W. O. and Sapolsky R. M. (2002) Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 4, 117128.
  • Lemos J. C., Pan Y. Z., Ma X., Lamy C., Akanwa A. C. and Beck S. G. (2006) Selective 5-HT receptor inhibition of glutamatergic and GABAergic synaptic activity in the rat dorsal and median raphe. Eur. J. Neurosci. 12, 34153430.
  • Leonard B. E. (2005) The HPA and immune axes in stress: the involvement of the serotonergic system. Eur. Psychiatry 13, S302S306.
  • Letty S., Lerner-Natoli M. and Rondouin G. (1995) Differential impairments of spatial memory and social behavior in two models of limbic epilepsy. Epilepsia 36, 973982.
  • Li L. M., Cendes F., Andermann F. et al. (1999) Surgical outcome in patients with epilepsy and dual pathology. Brain 122, 799805.
  • Lieberman D. N. and Mody I. (1999) Properties of single NMDA receptor channels in human dentate gyrus granule cells. J. Physiol. 518, 5570.
  • Liu Q. S., Xu Q., Arcuino G., Kang J. and Nedergaard M. (2004) Astrocyte-mediated activation of neuronal kainate receptors. Proc. Natl Acad. Sci. USA 101, 31723177.
  • Lu K. T. and Gean P. W. (1998) Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation. Neuroscience 86, 729737.
  • Mahanty N. K. and Sah P. (1999) Excitatory synaptic inputs to pyramidal neurons of the lateral amygdala. Eur. J.Neurosci. 11, 12171222.
  • Malmgren K., Starmark J. E., Ekstedt G., Rosen H. and Sjoberg-Larsson C. (2002) Nonorganic and organic psychiatric disorders in patients after epilepsy surgery. Epilepsy Behav. 3, 6775.
  • Malthankar-Phatak G. H., De Lanerolle N., Eid T., Spencer D. D., Behar K. L., Spencer S. S., Kim J. H. and Lai J. C. (2006) Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy. Epilepsia 47, 12921299.
  • Manno E. M., Sperling M. R., Ding X., Jaggi J., Alavi A., O’Connor M. J. and Reivich M. (1994) Predictors of outcome after anterior temporal lobectomy: positron emission tomography. Neurology 44, 23312336.
  • Mason B. L. and Pariante C. M. (2006) The effects of antidepressants on the hypothalamic-pituitary-adrenal axis. Drug News Perspect. 19, 603608.
  • Mathern G. W., Babb T. L., Micevych P. E., Blanco C. E. and Pretorius J. K. (1997) Granule cell mRNA levels for BDNF, NGF, and NT-3 correlate with neuron losses or supragranular mossy fiber sprouting in the chronically damaged and epileptic human hippocampus. Mol. Chem. Neuropathol. 30, 5376.
  • Matthews K., Christmas D., Swan J. and Sorrell E. (2005) Animal models of depression: navigating through the clinical fog. Neurosci. Biobehav. Rev. 29, 503513.
  • Mauguiere F. and Ryvlin P. (2004) The role of PET in presurgical assessment of partial epilepsies. Epileptic Disord. 6, 193215.
  • Mayberg H. S. (2003) Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin. N. Am. 13, 805815.
  • McEwan B. S. (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54, S20S23.
  • McIntyre D. C. (1978) Amygdala kindling and muricide rats. Physiol. Behav. 21, 4956.
  • Melo T. M., Nehlig A. and Sonnewald U. (2006) Metabolism is normal in astrocytes in chronically epileptic rats: a 13C NMR study of neuronal-glial interactions in a model of temporal lobe epilepsy. J. Cereb. Blood Flow Metab. 25, 12541264.
  • Merlet I., Ostrowsky K., Costes N., Ryvlin P., Isnard J., Faillenot I., Lavenne F., Dufournel D., Le Bars D. and Mauguiere F. (2004) 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study. Brain 127, 900913.
  • Meschaks A., Lindstrom P., Halldin C., Farde L. and Savic I. (2005) Regional reductions in serotonin 1A receptor binding in juvenile myoclonic epilepsy. Arch. Neurol. 62, 946960.
  • Mesquita A. R., Tavares H. B., Silva R. and Sousa N. (2006) Febrile convulsions in developing rats induce a hyperanxious phenotype later in life. Epilepsy Behav. 9, 401406.
  • Meyer J. H., Kapur S., Eisfeld B., Brown G. M., Houle S., DaSilva J., Wilson A. A., Rafi-Tari S., Mayberg H. S. and Kennedy S. H. (2001) The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am. J. Psychiatry 158, 7885.
  • Miller D. B. and O’Callaghan J. P. (2005) Aging, stress and the hippocampus. Ageing Res. Rev. 4, 123140.
  • Mirza Y., Tang J., Russell A., Banerjee S. P., Bhandari R., Ivey J., Rose M., Moore G. J. and Rosenberg D. R. (2004) Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. Am. Acad Child Adolesc. Psychiatry 43, 341348.
  • Moeller F. G., Barratt E. S., Dougherty D. M., Schmitz J. M. and Swann A. C. (2001) Psychiatric aspects of impulsivity. Am. J. Psychiatry 158, 17831793.
  • Monaco F., Cavanna A., Magli E., Barbagli D., Collimedaglia L., Cantello R. and Mula M. (2005) Obsessionality, obsessive–compulsive disorder, and temporal lobe epilepsy. Epilepsy Behav. 7, 491496.
  • Moresco R. M., Matarrese M. and Fazio F. (2006) PET and SPET molecular imaging: focus on serotonin system. Curr. Top. Med. Chem. 6, 20272034.
  • Mueller S. G., Laxer K. D., Schuff N. and Weiner M. W. (2007) Voxel-based T2 relaxation rate measurements in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis. Epilepsia 48, 220228.
  • Mula M., Trimble M. R. and Sander J. W. (2003) The role of hippocampal sclerosis in topiramate-related depression and cognitive deficits in people with epilepsy. Epilepsia 44, 15731577.
  • Muller B., Qu H., Garseth M., White L. R., Aasly J. and Sonnewald U. (2000) Amino acid neurotransmitter metabolism in neurones and glia following kainite injection in rats. Neurosci. Lett. 279, 169172.
  • Murray K. D., Isackson P. J., Eskin T. A., King M. A., Montesinos S. P., Abraham L. A. and Roper S. N. (2000) Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependant protein kinase in the hippocamapus of patients with intractable temporal lobe epilepsy. J. Comp. Neurol. 418, 411422.
  • Neder L., Valente V., Carlotti Jr C. G., Leite J. P., Assirati J. A., Paco-Larson M. L. and Moreira J. E. (2002) Glutamate NMDA receptor subunit R1 and GAD mRNA expression in human temporal lobe epilepsy. Cell. Mol. Neurobiol. 22, 689698.
  • Nedergaard M., Takano T. and Hansen A. J. (2002) Beyond the role of glutamate as a neurotransmitter. Nat. Rev. Neurosci. 3, 748755.
  • Nestler E. J., Barrot M., DiLeone R. J., Eisch A. J., Gold S. J. and Monteggia L. M. (2002) Neurobiology of depression. Neuron 34, 1325.
  • Neugebauer V., Keele N. B. and Shinnick-Gallagher P. (1997) Epileptogenesis in vivo enhances the sensitivity of inhibitory presynaptic metabotropic glutamate receptors in basolateral amygdala neurons in vitro. J. Neurosci. 17, 983995.
  • Neumeister A., Bain E., Nugent A. C., Carson R. E., Bonne O., Luckenbaugh D. A., Eckelman W., Herscovitch P., Charney D. S. and Drevets W. C. (2004) Reduced serotonin type 1A receptor binding in panic disorder. J. Neurosci. 24, 589591.
  • Nieminen S. A., Sirvio J., Teittinen K., Pitkanen A., Airaksinen M. M. and Riekkinen P. (1992) Amygdala kindling increased fear-response, but did not impair spatial memory in rats. Physiol. Behav. 51, 845849.
  • Nutt D. J. (2006) The role of dopamine and noradrenalin in depression and antidepressant treatment. J. Clin. Psychiatry 67, S3S8.
  • Ongur D., Drevets W. C. and Price J. L. (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl Acad. Sci. USA 95, 1329013295.
  • Oquendo M. A., Placidi G. P., Malone K. M. et al. (2003) Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression. Arch. Gen. Psychiatry 60, 1422.
  • Osehobo P., Adams B., Sazgar M., Xu Y., Racine R. J. and Fahnestock M. (1999) Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired-pulse measures of neuronal inhibition in adult rats. Neuroscience 92, 13671375.
  • Palucha A. (2006) Are compounds acting at metabotropic glutamate receptors the answer to treating depression? Expert Opin. Investig. Drugs 15, 15451553.
  • Parent J. M., Von Dem Bussche N. and Lowenstein D. H. (2006) Prolonged seizures recruit caudal subventricular zone glial progenitors into the njured hippocampus. Hippocampus 16, 321328.
  • Pasini A., Tortorella A. and Gale K. (1996) The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res. 724, 8488.
  • Paul I. A. and Skolnick P. (2003) Glutamate and depression: clinical and preclinical studies. Ann. N. Y. Acad. Sci. 1003, 250272.
  • Petroff O. A., Errante L. D., Rothman D. L., Kim J. H. and Spencer D. D. (2002a) Glutamate-glutamine cycling in the epileptic human hippocampus. Epilepsia 43, 703710.
  • Petroff O. A., Errante L. D., Rothman D. L., Kim J. H. and Spencer D. D. (2002b) Neuronal and glial metabolite content of the epileptogenic human hippocampus. Ann. Neurol. 52, 635642.
  • Phelps E. A. and LeDoux J. E. (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175187.
  • Pintor L., Bailles E., Fernandez-Egea E. et al. (2007) Psychiatric disorders in temporal lobe epilepsy patients over the first year after surgical treatment. Seizure 16, 218225.
  • Pompili M., Girardi P. and Tatarelli R. (2006) Death from suicide versus mortality from epilepsy in the epilepsies: a meta-analysis. Epilepsy Behav. 4, 641648.
  • Popova N. K. (2006) From genes to aggressive behavior: the role of serotonergic system. Bioessays 2006, 495503.
  • Prasher V. P. (1993) Seizure associated with fluoxetine therapy. Seizure 2, 315317.
  • Pritchard P. B. (1991) Effects of seizures on hormones. Epilepsia 32, S46S50.
  • Pugliese A. M., Passani M. B. and Corradetti R. (1998) Effect of the selective 5-HT1A receptor antagonist WAY 100635 on the inhibition of produced by 5-HT in the CA1 region of rat hippocampal slices. Br. J. Pharmacol. 124, 93100.
  • Pulsipher D. T., Seidenberg M., Jones J. and Hermann B. (2006) Quality of life and comorbid medical and psychiatric conditions in temporal lobe epilepsy. Epilepsy Behav. 3, 510514.
  • Qu H., Eloqayli H., Muller B., Aasly J. and Sonnewald U. (2003) Glial-neuronal interactions following kainate injection in rats. Neurochem. Int. 42, 101106.
  • Quiske A., Helmstaedter C., Lux S. and Elger C. E. (2000) Depression in patients with temporal lobe epilepsy is related to mesial temporal sclerosis. Epilepsy Res. 39, 121125.
  • Rainnie D. G. (1999) Serotonergic modulation of neurotransmission in the rat basolateral amygdala. J. Neurophysiol. 82, 6985.
  • Rainnie D. G., Asprodini E. K. and Shinnick-Gallagher P. (1991) Inhibitory transmission in the basolateral amygdala. J. Neurophysiol. 66, 9991009.
  • Rajkowska G. and Miguel-Hidalgo J. J. (2007) Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets 6, 219233.
  • Ramboz S., Saudou F., Amara D. A., Belzung C., Segu L., Misslin R., Buhot M. C. and Hen R. (1996) 5-HT1B receptor knock out--behavioral consequences. Behav. Brain Res. 73, 305312.
  • Rasmuson S., Andrew R., Nasman B., Seckl J. R., Walker R. B. and Olsson T. (2001) Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease. Biol. Psychiatry 49, 547552.
  • Reibel S., Larmet Y., Carnahan J., Marescaux C. and Depaulis A. (2000a) Brain-derived neurotrophic factor delays hippocampal kindling in the rat. Neuroscience 100, 777788.
  • Reibel S., Vivien-Roels B., Le B. T., Larmet Y., Carnahan J., Marescaux C. and Depaulis A. (2000b) Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting. Eur. J. Neurosci. 12, 595605.
  • Reuber M., Andersen B., Elger C. E. and Helmstaedter C. (2004) Depression and anxiety before and after temporal lobe epilepsy surgery. Seizure 13, 129135.
  • Richardson E. J., Griffith H. R., Martin R. C., Paige A. L., Stewart C. C., Jones J., Hermann B. P. and Seidenberg M. (2007) Structural and functional neuroimaging correlates of depression in temporal lobe epilepsy. Epilepsy Behav. 10, 242249.
  • Roch C., Leroy C., Nehlig A. and Namer I. J. (2002) Predictive value of cortical injury for the development of temporal lobe epilepsy in 21-day-old rats: an MRI approach using the lithium-pilocarpine model. Epilepsia 43, 11291136.
  • Rogan M. T., Staubli U. V. and LeDoux J. E. (1997) Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604607.
  • Rogawski M. A. (2005) Astrocytes get in the act in epilepsy. Nat. Med. 11, 919920.
  • Russo-Neustadt A. A. and Chen M. J. (2005) Brain-derived neurotrophic factor and antidepressant activity. Curr. Pharm. Des. 11, 14951510.
  • Salzberg M., Taher T., Davie M., Carne R., Hicks R. J., Cook M., Murphy M., Vinton A. and O’Brien T. J. (2006) Depression in temporal lobe epilepsy surgery patients: an FDG-PET study. Epilepsia 47, 21252130.
  • Sanacora G., Kendell S. F., Levin Y., Simen A. A., Fenton L. R., Coric V. and Krystal J. H. (2007) Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol. Psychiatry 61, 822825.
  • Sapolsky R. M. (2000) Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch. Gen. Psychiatry 57, 925935.
  • Sargent P. A., Kjaer K. H., Bench C. J., Rabiner E. A., Messa C., Meyer J., Gunn R. N., Grasby P. M. and Cowen P. J. (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch. Gen. Psychiatry 57, 174180.
  • Savic I., Lindstrom P., Gulyas B., Halldin C., Andree B. and Farde L. (2004) Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology 62, 13431351.
  • Scharfman H. E. (2005) Brain-derived neurotrophic factor and epilepsy-a missing link? Epilepsy Curr. 5, 8388.
  • Scharfman H. E., Goodman J. H., Sollas A. L. and Croll S. D. (2002) Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp. Neurol. 174, 201214.
  • Schousboe A. (2003) Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem. Res. 28, 347352.
  • Schubert M., Siegmund H., Pape H. C. and Albrecht D. (2005) Kindling-induced changes in plasticity of the rat amygdala and Hippocamopus. Learn. Mem. 12, 520526.
  • Seiffert E., Dreier J. P., Ivens S., Bechmann I., Tomkins O., Heinemann U. and Friedman A. (2004) Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 78297836.
  • Semah F. (2002) Temporopolar metabolic abnormalities in temporal lobe epilepsies. Epileptic Disord. 4, S41S49.
  • Semah F., Baulac M., Hasboun D., Frouin V., Mangin J. F., Papageorgiou S., Leroy-Willig A., Philippon J., Laplane D. and Samson Y. (1995) Is interictal temporal hypometabolism related to mesial temporal sclerosis? A positron mission tomography/magnetic resonance imaging confrontation. Epilepsia 36, 447456.
  • Shank R. P., Bennett G. S., Freytag S. O. and Campbell G. L. (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res. 329, 364367.
  • Sheline Y. I. (2003) Neuroimaging studies of mood disorder effects on the brain. Biol. Psychiatry 54, 338352.
  • Sheline Y. I., Wang P. W., Gado M. H., Csernansky J. G. and Vannier M. W. (1996) Hippocampal atrophy in recurrent major depression. Proc. Natl Acad. Sci. USA 93, 39083913.
  • Sheline Y. I., Gado M. H. and Price J. L. (1998) Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport 9, 50345043.
  • Sheline Y. I., Sanghavi M., Mintun M. A. and Gado M. H. (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19, 50345043.
  • Sher L., Carballo J. J., Grunebaum M. F., Burke A. K., Zalsman G., Huang Y. Y., Mann J. J. and Oquendo M. A. (2006) A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder. Bipolar Disord. 8, 543550.
  • Shirayama Y., Chen A. C., Nakagawa S., Russell D. S. and Duman R. S. (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 32513261.
  • Siuciak J. A., Lewis D. R., Wiegand S. J. and Lindsay R. M. (1997) Antidepressant- like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56, 131137.
  • Siva N. (2005) Astrocytes have a key role in epilepsy. Lancet Neurol. 4, 601.
  • Smythies J. (2005) Section III. The noradrenalin system. Int. Rev. Neurobiol. 64, 173211.
  • Sokolowski J. D. and Seiden L. S. (1999) The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat. Psychopharmacol. 147, 153161.
  • Sonnewald U. and Kondziella D. (2003) Neuronal glial interaction in different neurological diseases studied by ex vivo 13C NMR spectroscopy. NMR Biomed. 16, 424429.
  • Spencer S. (2007) Epilepsy: clinical observations and novel mechanisms. Lancet Neurol. 6, 1416.
  • Stachowicz K., Chojnacka-Wojcik E., Klak K. and Pilc A. (2006) Anxiolytic-like effects of group III mGlu receptor ligands in the hippocampus involve GABA(A) signaling. Pharmacol. Rep. 58, 820826.
  • Stachowicz K., Chojnacka-Wojcik E., Klak K. and Pilc A. (2007) Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent. Neuropharmacol. 52, 306312.
  • Stanford M. S., Helfritz L. E., Conklin S. M., Villemarette-Pittman N. R., Greve K. W., Adams D. and Houston R. J. (2005) A comparison of anticonvulsants in the treatment of impulsive aggression. Exp. Clin. Psychopharmacol. 13, 7277.
  • Szabo G., Kartarova Z., Hoertnagl B., Somogyi R. and Sperk G. (2000) Differential regulation of adult and embryonic glutamate decarboxylases in rat dentate granule cells after kainate-induced limbic seizures. Neuroscience 100, 287295.
  • Szyndler J., Wierzba-Bobrowicz T., Skorzewska A., Maciejak P., Walkowiak J., Lechowicz W., Turzynska D., Bidzinski A. and Plaznik A. (2005) Behavioral, biochemical and histological studies in a model of pilocarpine-induced spontaneous recurrent seizures. Pharmacol. Biochem. Behav. 81, 1523.
  • Takeshita H., Kawahara R., Nagabuchi T., Mizukawa R. and Hazama H. (1986) Serum prolactin and growth hormone concentrations after various epileptic seizures. Jpn. J. Psychiatry Neurol. 40, 617623.
  • Tardito D., Perez J., Tiraboschi E., Musazzi L., Racagni G. and Popoli M. (2006) Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol. Rev. 58, 115134.
  • Tata D. A., Marciano V. A. and Anderson B. J. (2006) Synapse loss from chronically elevated glucocorticoids: relationship to neuropil volume and cell number in hippocampal area CA3. J. Comp. Neurol. 498, 363374.
  • Tebartz van Elst L., Woermann F. G., Lemieux L. and Trimble M. R. (1999) Amygdala enlargement in dysthymia: a volumetric study of patients with temporal lobe epilepsy. Biol. Psychiatry 46, 16141623.
  • Tebartz van Elst L., Woermann F., Lemieux L. and Trimble M. R. (2000) Increased amygdala volumes in female and depressed humans: a quantitative magnetic resonance imaging study. Neurosci. Lett. 281, 103106.
  • Then Bergh F., Kumpfel T., Grasser A., Rupprecht R., Holsboer F. and Trenkwalder C. (2001) Combined treatment with corticosetroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double-blind trial. J. Clin. Endocrinol. Metab. 86, 16101615.
  • Thome-Souza M. S., Kuczynski E. and Valente K. D. (2007) Sertraline and fluoxetine: Safe treatments for children and adolescents with epilepsy and depression. Epilepsy Behav. [Epub ahead of print].
  • Tian G. F., Azmi H., Takano T. et al. (2005) An astrocytic basis of epilepsy. Nat. Med. 11, 973981.
  • Tobianski R. I. and Lloyd G. G. (1995) ECG seizure threshold and fluoxetine. Br. J. Psychiatry 166, 263270.
  • Toczek M. T., Carson R. E., Lang L. et al. (2003) PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 60, 749756.
  • Tordera R. M., Totterdell S., Wojcik S. M., Brose N., Elizalde N., Lasheras B. and Del Rio J. (2007) Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 (VGLUT1). Eur. J. Neurosci. 25, 281290.
  • Tran P. V., Bymaster F. P., McNamara R. K. and Potter W. Z. (2003) Dual monoamine modulation for improved treatment of major depressive disorder. J. Clin. Psychopharmacol. 23, 7886.
  • Verkhratsky A. and Toescu E. C. (2006) Neuronal-glial networks as substrate for CNS integration. J. Cell. Mol. Med. 10, 826836.
  • Victoroff J. I., Benson F., Grafton S. T., Engel J. and Mazziotta J. C. (1994) Electroencephalography and cerebral metabolic correlates. Arch. Neurol. 51, 155163.
  • Vinton A. B., Carne R., Hicks R. J., Desmond P. M., Kilpatrick C., Kaye A. H. and O’Brien T. J. (2007) The extent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy. Brain 130, 548560.
  • Volterra A. and Meldolesi J. (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat. Rev. Neurosci. 6, 626640.
  • Voutsinos-Porche B., Koning E., Clement Y., Kaplan H., Ferrandon A., Motte J. and Nehlig A. (2006) EAAC1 glutamate transporter expression in the rat lithium-pilocarpine model of temporal lobe epilepsy. J. Cereb. Blood Flow Metab. 26, 14191430.
  • Vreugdenhil M., Hoogland G., Van Veelen C. W. and Wadman W. J. (2004) Persistent sodium current in subicular neurons isolated from patients with temporal lobe epilepsy. Eur. J. Neurosci. 19, 27692778.
  • Vyas A., Mitra R., Shankaranarayana Rao B. S. and Chattarju S. (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 68106818.
  • Weiss S. R. B., Post R. M., Gold P. W., Chrousos G., Sullivan T. L., Walker D. and Pert A. (1986) CRF-induced seizures and behavior: interaction with amygdala kindling. Brain Res. 372, 345351.
  • Wu C. L., Huang L. T., Liou C. W., Wang T. J., Tung Y. R., Hsu H. Y. and Lai M. C. (2001) Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss. Neurosci. Lett. 312, 113117.
  • Wuerfel J., Krishnamoorthy E. S., Brown R. J., Lemieux L., Koepp M., Tebartz van Elst L. and Trimble M. R. (2004) Religiosity is associated with hippocampal but not amygdala volumes in patients with refractory epilepsy. J. Neurol. Neurosurg. Psychiatry 75, 640642.
  • Yamamoto S., Miyamoto T., Morita N. and Yasuda M. (2002) Depressive disorders preceeding temporal lobe epilepsy. Epilepsy Res. 49, 153156.
  • Yan Q. S., Jobe P. C., Cheong J. H., Ko K. H. and Dailey J. W. (1994a) Role of serotonin in the anticonvulsive effect of fluoxetine in genetically epilepsy-prone rats. Arch. Pharmacol. 350, 149152.
  • Yan Q. S., Jobe P. C. and Dailey J. W. (1994b) Evidence that a serotonergic mechanism is involved in the antiepileptic effect of fluoxetine in genetically epilepsy-prone rats. Eur. J. Pharmacol. 252, 105112.
  • Young A. H. (2006) Antiglucocoticoid treatments for depression. Aust. N. Z. J. Psychiatry 40, 402405.
  • Zhu W. J. and Roper S. N. (2001) Brain-derived neurotrophic factor enhances fast excitatory synaptic transmission in human epileptic dentate gyrus. Ann. Neurol. 50, 188194.
  • Zobel A., Wellmer J., Schulze-Rauschenbach S., Pfeiffer U., Schnell S., Elger C. and Maier W. (2004) Impairment of inhibitory control of the hypothalamic pituitary adrenocortical system in epilepsy. Eur. Arch. Psychiatry Clin. Neurosci. 254, 303311.