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Keywords:

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

Abstract

  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
5-HT

serotonin

ACTH

adrenocorticotropin

AED

antiepileptic drug

BDNF

brain derived neurotrophic factor

CRF

corticotropin-releasing factor

FDG

fluorodeoxyglucose

HPA

hypothalamic-pituitary-adrenal

mGluR

metabotropic glutamate receptors

MRI

Magnetic Resonance Imaging

MRS

Magnetic Resonance Spectroscopy

PET

positron emission tomography

SSRI

serotonin re-uptake inhibitor

TLE

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.

image

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.

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  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
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