SEARCH

SEARCH BY CITATION

Keywords:

  • Adult neurogenesis;
  • Aberrant migration of newly born neurons;
  • Cognitive dysfunction;
  • Dentate neurogenesis;
  • Depression;
  • Granule cells;
  • Learning and memory;
  • Neural stem cells;
  • Spontaneous seizures;
  • Stem cell proliferation;
  • Stem cell differentiation;
  • Temporal lobe epilepsy

Summary

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent motor seizures (SRMS), learning and memory impairments, and depression, is associated with neurodegeneration, abnormal reorganization of the circuitry, and loss of functional inhibition in the hippocampal and extrahippocampal regions. Over the last decade, abnormal neurogenesis in the dentate gyrus (DG) has emerged as another hallmark of TLE. Increased DG neurogenesis and recruitment of newly born neurons into the epileptogenic hippocampal circuitry is a characteristic phenomenon occurring during the early phase after the initial precipitating injury such as status epilepticus. However, the chronic phase of the disease displays substantially declined DG neurogenesis, which is associated with SRMS, learning and memory impairments, and depression. This review focuses on DG neurogenesis in the chronic phase of TLE and first confers the extent and mechanisms of declined DG neurogenesis in chronic TLE. The available data on production, survival and neuronal fate choice decision of newly born cells, stability of hippocampal stem cell numbers, and changes in the hippocampal microenvironment in chronic TLE are considered. The next section discusses the possible contribution of declined DG neurogenesis to the pathophysiology of chronic TLE, which includes its potential effects on spontaneous recurrent seizures, cognitive dysfunction, and depression. The subsequent section considers strategies that may be useful for augmenting DG neurogenesis in chronic TLE, which encompass stem cell grafting, administration of distinct neurotrophic factors, physical exercise, exposure to enriched environment, and antidepressant therapy. The final section suggests possible ramifications of increasing the DG neurogenesis in chronic epilepsy.

Epilepsy is one of the common neurological disorders after stroke and afflicts nearly 50 million people worldwide. Interruptions in the normal electrical activity and abnormal wiring are prominent features of the epileptic brain. These changes facilitate simultaneous firing of high-amplitude action potentials from multiple groups of neurons leading to an electrical storm within the brain that eventually results in motor seizures. Temporal lobe epilepsy (TLE) is observed in about 40% of patients with epilepsy, where spontaneous recurrent seizures originate from the temporal lobe, particularly the hippocampus (French et al., 1993; Engel et al., 2003a, 2003b). The precise causes of TLE are unknown in most cases. However, it is believed that TLE with hippocampal sclerosis occurs after an initial precipitating injury (IPI) such as brain injury, tumors, meningitis, encephalitis, status epilepticus (SE), or febrile seizures during childhood (Engel et al., 1989; French et al., 1993; Mathern et al., 1995, 1996; Harvey et al., 1997; Fisher et al., 1998; Cendes, 2004; Wieser, 2004; Lewis, 2005). Evaluation of brain tissues from humans with TLE and studies in animal models have shown that TLE is characterized by various changes in the hippocampus that include partial degeneration of CA1 and CA3 pyramidal neurons and dentate hilar neurons (Sutula et al., 1989; Dalby & Mody, 2001; Buckmaster et al., 2002; Rao et al., 2006a), reductions in gamma-amino butyric acid-positive (GABAergic) interneurons (Sloviter, 1987; Franck et al., 1988; Shetty & Turner, 2000, 2001), loss of functional inhibition (Cornish & Wheal, 1989; Perez et al., 1996; Dudek & Sutula, 2007), disappearance of the calcium-binding protein calbindin in a substantial fraction of dentate granule cells (Nagerl et al., 2000; Shetty & Hattiangady, 2007a), and aberrant sprouting and reorganization of dentate granule cell, entorhinal, and CA3 axons (Tauck & Nadler, 1985; Sutula et al., 1989; Houser, 1990; Shetty & Turner, 1997a, 1999a; Shetty, 2002; Shetty et al., 2003, 2005a; Siddiqui & Joseph, 2005; Wozny et al., 2005). All of these changes are hypothesized to contribute to the development of chronic epilepsy, characterized by unpredictable occurrence of spontaneous recurrent motor seizures (SRMS). Furthermore, most TLE patients show learning and memory impairments and depression Devinsky, 2004; Helmstaedter et al., 2004; Mazza et al., 2004; Detour et al., 2005).

Over the last decade, altered dentate neurogenesis has emerged as another hallmark of TLE. This alteration consists of an increase in neurogenesis in the dentate gyrus (DG) and an abnormal migration of a substantial fraction of newly generated granule cells from the subgranular zone (SGZ) into the dentate hilus during the early phase after the IPI such as SE (Houser, 1990; Bengzon et al., 1997; Parent et al., 1997; Nakagawa et al., 2000; Scharfman et al., 2000; Scott et al., 2000; Ekdahl et al., 2001; Parent & Lowenstein, 2002; Scharfman et al., 2002, 2003; McCloskey et al., 2006; Parent et al., 2006; Gong et al., 2007; Parent, 2007; Scharfman & Hen, 2007). However, the chronic phase of the disease displays substantially declined DG neurogenesis (Hattiangady et al., 2004) that is associated with SRMS, learning and memory impairments, and depression (Miller et al., 1993; Letty et al., 1995; Schwarcz & Witter, 2002; Rao et al., 2006a, 2007; Kondziella et al., 2007). Dentate neurogenesis normally occurs throughout life in all species including humans (Kuhn et al., 1996; Gould et al., 1997; Eriksson et al., 1998; Gould et al., 1999; Kornack & Rakic, 1999; Guidi et al., 2005). The enormity of dentate neurogenesis exhibits a close relationship with the hippocampal functions of learning and memory (Gross, 2000; Feng et al., 2001; Shors et al., 2001; van Praag et al., 2002; Aimone et al., 2006). This is evidenced by the association between decreased DG neurogenesis and impairments in some of the hippocampal-dependent learning and memory functions (Drapeau et al., 2003; Rola et al., 2004; Bruel-Jungerman et al., 2005; Dalla et al., 2007; Siwak-Tapp et al., 2007). Furthermore, increased dentate neurogenesis is considered important for mediating some of the behavioral effects of antidepressants in major depressive disorders (Santarelli et al., 2003; Sahay & Hen, 2007).

Because of its disparate response in the early and chronic stages of the disease, DG neurogenesis has received considerable attention in terms of understanding the pathophysiology of TLE. Studies suggest that granule cells that migrate into the dentate hilus during the early phase after the IPI get integrated abnormally into the CA3 network (Scharfman et al., 2000), get activated when epileptic rats exhibit spontaneous seizures (Scharfman et al., 2002; Jessberger et al., 2007), and respond to perforant path stimulation with a longer latency to onset of evoked responses (Scharfman et al., 2003). Additionally, studies demonstrate that these ectopically placed granule cells establish afferent connectivity with mossy fiber terminals (Pierce et al., 2005), exhibit spontaneous bursts of action potentials (Scharfman et al., 2000), and likely contribute to SRMS in chronically epileptic animals (Jung et al., 2004; McCloskey et al., 2006). These issues are detailed in recent reviews on this topic (Parent, 2007; Scharfman & Gray, 2007). Therefore, in this review, we focus on DG neurogenesis during the chronic phase of TLE. The first section of this review confers the extent and mechanisms of declined DG neurogenesis in chronic TLE. The next segment discusses whether the declined DG neurogenesis contributes to the pathophysiology of chronic TLE. The subsequent section considers feasible strategies that may be useful for augmenting DG neurogenesis in chronic TLE. The final segment discusses the potential implications of increased DG neurogenesis in the chronic phase of TLE.

Extent of Dentate Neurogenesis in Chronic TLE

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

A series of epileptogenic changes ensue in the hippocampus after an IPI such as SE. These changes lead to hyperexcitability in the DG as well as in the CA1 subfield that eventually evolves into a chronic epileptic state typified by SRMS (Dudek & Sutula, 2007). At early time points after SE, the DG neurogenesis is characterized by dramatic increases in the production of new neurons and aberrant migration of a substantial fraction of newly born neurons into the dentate hilus and the molecular layer (Parent, 2007; Scharfman & Gray, 2007). However, the initial seizure-induced increase in DG neurogenesis returns to the baseline by about 2 months after SE in rats (Jessberger et al., 2007) and reaches substantially below the baseline level by 5 months after SE (Hattiangady et al., 2004). The extent of DG neurogenesis has been assessed in animal models of chronic TLE as well as in human TLE. The amount of decrease and changes in different aspects of neurogenesis in chronic epilepsy are discussed in the following sections.

Dentate neurogenesis in animal models of chronic TLE

The dentate neurogenesis has been examined rigorously in two different kainic acid (KA) models of chronic TLE in rats (Hattiangady et al., 2004, 2005a). The first model is a unilateral intracerebroventricular (ICV) KA model in which administration of 0.5 μg of KA directly into the posterior lateral ventricle under anesthesia induces extensive degeneration of CA3 pyramidal neurons and loss of sizable fraction of dentate hilar neurons in the hippocampus ipsilateral to the KA administration (Shetty & Turner, 1995, 1996, 1997a, 1997b, 1999a, 1999b). Following this injury, multiple epileptogenic changes occur in both DG and CA1 subfield, resulting in hippocampal hyperexcitability (Turner & Wheal, 1991; Shetty & Turner, 1997a, 1999a, 2000, 2001; Shetty et al., 2003, 2005a). However, because of the unilateral nature of the injury, the frequency of SRMS has been found to be minimal in this model (Hattiangady et al., 2004). The other model is an intraperitoneal (IP) KA model in which graded IP injections of KA at a dose of 3 mg/kg body weight (BW) (once every hour for 3–5 h) induces continuous stages III–V seizures for over 3 h, resulting in bilateral loss of fractions of neurons in the dentate hilus and CA1 and CA3 subfields of the hippocampus (Hattiangady et al., 2004, 2005a; Rao et al., 2006a). This injury also induces multiple epileptogenic changes in the hippocampus during the silent phase that eventually culminate in chronic epilepsy characterized by robust SRMS (Rao et al., 2006a, 2007), learning and memory deficits, and depression (Stafstrom et al., 1993; Mikati et al., 2001). Interestingly, DG neurogenesis declines substantially when animals exhibit chronic epilepsy in both models.

Status of neurogenesis assessed through doublecortin expressing newly generated neurons

Analyses of the status of DG neurogenesis through stereological measurement of cells expressing doublecortin (DCX, a marker of newly born neurons; Rao & Shetty, 2004) at early and delayed time points after the hippocampal injury induced through KA revealed that DG neurogenesis declines substantially in animals exhibiting chronic TLE (Hattiangady et al., 2004). Interestingly, DG neurogenesis declined in both ICV KA and IP KA models of TLE at 5 months post-KA administration (Fig. 1), though the frequency of SRMS varied considerably between these two models. The overall reductions in the addition of new neurons in the chronically epileptic hippocampus ranged from 64% to 81%, in comparison to the hippocampus from age-matched control rats (Fig. 1). However, the extent of decrease in DG neurogenesis was considerably more pronounced in rats exhibiting greater frequency of SRMS (81% decline) than rats exhibiting much fewer SRMS (64% decline). Likewise, the ectopic migration of newly born granule cells was greater (54% of all DCX-positive neurons) in rats exhibiting greater frequency of SRMS than rats displaying fewer SRMS (31% of all DCX-positive neurons). Moreover, unlike the DCX-positive neurons in the age-matched control hippocampus exhibiting apical dendrites projecting into the molecular layer, a vast majority of DCX-positive neurons located in and around the SGZ of the chronically epileptic hippocampus exhibited basal dendrites (Fig. 1), a feature believed to contribute toward the establishment of recurrent excitatory circuitry (Ribak et al., 2000). Interestingly, this feature is consistent with the dendritic morphology of a majority of newly born neurons generated at early time points after SE (Dashtipour et al., 2003; Shapiro et al., 2005; Shapiro & Ribak, 2006; Ribak & Shapiro, 2007; Walter et al., 2007). These results imply that a greater frequency of seizures in chronic epilepsy is detrimental for both the production of new granule cells from neural stem/progenitor cells (NSCs) in the SGZ as well as for the normal migration and polarity of newly generated granule cells.

image

Figure 1. Status of dentate neurogenesis during chronic epilepsy as revealed by doublecortin (DCX) immunostaining. A1–C1 illustrate the distribution of DCX-positive newly born neurons in the dentate gyrus of an age-matched intact rat (A1), a rat exhibiting chronic epilepsy at 5 months after an intracerebroventricular (ICV) kainic acid (KA) administration (B1), and a rat displaying robust chronic epilepsy at 5 months after intraperitoneal (IP) KA-induced status epilepticus (SE) (C1). Note that, in comparison to the age-matched intact hippocampus, hippocampi from chronically epileptic animals exhibit dramatically reduced density of DCX-positive newly generated neurons. Arrowheads point to regions in the subgranular zone (SGZ) where neurogenesis is active. The arrow in C1 denotes a neuron that has migrated into the dentate hilus. A2, B2, and C2 are magnified views of regions from A1, B1, and C1, respectively, demonstrating the morphology of newly generated neurons in the three groups. In the dentate gyrus of the age-matched intact rat (A2), DCX-positive new neurons exhibit long apical dendrites that extend into the molecular layer (ML) through the granule cell layer (GCL). Contrastingly, in hippocampi from epileptic animals (B2, C2), vast majority of DCX-positive neurons display basal dendrites (indicated by short arrows). The bar chart compares the absolute numbers of DCX-positive new neurons in different groups. Note that, in comparison to the age-matched control rats, the overall dentate neurogenesis in hippocampi of chronically epileptic rats is drastically reduced. Furthermore, the decline is more pronounced in the hippocampus of rats exhibiting robust chronic epilepsy (i.e., the hippocampus at 5-month post-SE) than the hippocampus of rats exhibiting fewer spontaneous seizures (i.e., the hippocampus at 5-month post-ICV KA administration). DH, dentate hilus; GCL, granule cell layer. Scale bar: A1, B1, C1= 200 μm; A2, B2, C2= 50 μm.

Download figure to PowerPoint

Dramatically decreased DG neurogenesis in chronic epilepsy observed by Hattiangady et al. (2004) has been confirmed by another study (Heinrich et al., 2006), where both decreased numbers of DCX-positive neurons and reduced levels of mRNA for DCX were observed in the KA-injected hippocampus. In this model, there was a gradual fall in neurogenesis at 1 week and virtual loss of all DCX-positive neurons by 4–6 weeks after KA administration, which paralleled granule cell dispersion and widening of granule cell layer (GCL). However, the timeline for the loss of DCX-positive neurons in the SGZ-GCL after an IPI varies depending on the animal model employed. For instance, a study by Bonde et al. (2006), using an electrically evoked SE model, shows production of DCX-positive neurons in the dorsal hippocampus to levels found in the age-matched intact hippocampus at 6 months post-SE. Similarly, Cha et al. (2004), using lithium-pilocarpine model of SE in postnatal day 20 rats, demonstrated a modest increase in DG neurogenesis at 2 months after SE. Thus, the decline in DG neurogenesis in chronic epilepsy depends also on the age of the animal at the time of initial insult such as SE or severe hippocampal injury. Adult animals seem to be more prone to severe loss of neurogenesis in chronic epilepsy (Hattiangady et al., 2004; Heinrich et al., 2006) than younger animals (Cha et al., 2004). Additionally, the status of DG neurogenesis during chronic epilepsy also depends upon the severity of SRMS and hippocampal injury. Animals exhibiting greater frequency and intensity of SRMS and/or severe hippocampal injury exhibit more dramatic loss of DG neurogenesis than animals exhibiting lower frequency of SRMS and minimal hippocampal injury (Hattiangady et al., 2004; Bonde et al., 2006; Heinrich et al., 2006).

Addition, survival, and neuronal differentiation of newly born cells in the GCL

Addition of new cells to the GCL over a period of 12 days in animals exhibiting chronic TLE has been analyzed using birth-dating markers such as the 5′-bromodeoxyuridine (BrdU) (Hattiangady et al., 2005a). The results demonstrated that the overall addition of new cells to the SGZ-GCL in chronic TLE is similar to that observed in the age-matched intact hippocampus, implying that chronic epilepsy does not interfere with the production of new cells in the SGZ-GCL. Further analyses revealed comparable long-term survival of newly born cells (∼55–59% of newly produced cells) between the chronically epileptic hippocampus and the age-matched intact hippocampus (Hattiangady et al., 2005a). These results suggest that the microenvironment of the chronically epileptic hippocampus is adequate for supporting the long-term survival of newly born cells to levels observed in the age-matched intact hippocampus. However, additional analyses revealed that chronic TLE is associated with considerable (95%) decline in neuronal differentiation of newly born cells (Hattiangady et al., 2005a). Kralic and colleagues (2005), using an ICV KA model of epilepsy in mouse exhibiting hippocampal sclerosis and granule cell dispersion, have also found similar results. In this model, a vast majority (70–90%) of newly born cells in the SGZ of the injured hippocampus differentiated into glia in comparison to the age-matched intact hippocampus where ∼75% of newly born cells differentiated into neurons (Kralic et al., 2005). Thus, while chronic epilepsy is associated with no changes in the production or survival of newly born cells, it does appear to interfere with the neuronal fate choice decision of newly generated cells.

Dentate neurogenesis in human TLE

Decreased DG neurogenesis observed in animal models of chronic TLE is also supported by the findings in hippocampal tissues resected from human TLE patients (Mathern et al., 2002; Crespel et al., 2005; Pirttila et al., 2005a, 2005b; and see review by Siebzehnrubl and Blumcke, 2008). It also appeared that the extent of decline in neurogenesis is directly proportional to the severity of lesion in chronic TLE (Mikkonen et al., 1998). A recent study confirms decreased DG neurogenesis in TLE patients through observation of decreased synthesis of mRNA for DCX (Fahrner et al., 2007) and absence of cells positive for Ki-67 (a marker of proliferating cells). Thus, studies in hippocampi of both TLE patients and animals exhibiting chronic TLE clearly suggest that DG neurogenesis substantially declines in chronic epilepsy.

Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

A different scenario of DG neurogenesis during chronic epilepsy in comparison to its status shortly after SE suggests that multiple changes that progress after an IPI are not conducive for the production of new neurons by NSCs in the SGZ (Fig. 2). This could be due to changes in the number of NSCs in the SGZ and/or changes in the DG microenvironment. The following sections examine each of these issues in detail.

image

Figure 2. Events leading to radically decreased dentate neurogenesis during chronic epilepsy. Initial precipitating injury such as acute seizures, status epilepticus, etc., leads to chronic epilepsy development through a phase called the silent period. During the silent period, multiple epileptogenic changes occur, which mainly include increased levels of multiple neurotrophic factors, aberrant synaptic reorganization in the dentate gyrus and CA1 subfield, reductions in hippocampal GABA-ergic interneuron numbers, loss of functional inhibition, and upregulation of dentate neurogenesis with aberrant migration of substantial fraction of newly born neurons into the dentate hilus. However, during chronic epilepsy, the microenvironment of hippocampus exhibits further alterations in the form of decreased levels of multiple neurotrophic factors (e.g., BDNF, FGF-2, and IGF-1), reduced expression of reelin, and increased levels of cystatin C. Inflammation also persists, though it is reduced compared to early time points after the initial precipitating injury. Interestingly, neural stem/progenitor cells (NSCs) survive in this altered microenvironment, exhibit significant proliferation, and produce new cells to levels seen in the age-matched intact hippocampus. However, the altered microenvironment interferes with the neuronal differentiation of newly born cells, as only 4% of new cells differentiate into neurons, in comparison to 80% of new cells differentiating into neurons in the age-matched intact hippocampus. Thus, radically diminished neurogenesis during chronic epilepsy is a consequence of dramatic decrease in the neuronal differentiation of newly born cells, which is likely influenced by altered microenvironment. Considering the functions of adult neurogenesis, it is possible that decreased neurogenesis at least partially contributes to learning and memory impairments and depression observed during chronic epilepsy. However, decreased concentration of various neurotrophic factors and frequent spontaneous seizures likely also influence learning and memory function and depression.

Download figure to PowerPoint

Alterations in hippocampal stem cell number

A recent study suggests that the numbers of putative NSCs that are immunopositive for the transcription factor sex determining region of Y-chromosome-2 (Sox2) decline by ∼30% in the SGZ of rats exhibiting chronic TLE (Shetty, personal communication). This finding also corroborated with the counts of cells positive for vimentin (i.e., radial glial cells or putative stem cells) in the dentate SGZ-GCL (Shetty, personal communication). These results are, however, in contrast to the human study, where an increased number of cells positive for Musashi-1 (another marker of putative NSCs) was seen in the epileptic hippocampal tissues obtained from TLE patients (Crespel et al., 2005). Most of the Musashi-1-positive cells in this study were found in the SGZ and the hippocampal fissure. Many Musashi-1-positive cells also coexpressed vimentin or nestin, suggesting that these cells are likely NSCs. Musashi-1 is known to potentiate notch signaling that maintains NSCs in an undifferentiated state in pathological conditions (Morrison, 2001) or instructs them to proliferate and differentiate into glia (Imai et al., 2001; Okano et al., 2002) in control conditions. Based on these characteristics, Crespel and colleagues (2005) suggest that increased expression of Musashi-1 during chronic epilepsy instructs NSCs to remain in an undifferentiated state and/or to switch into glial fate. Either or both of these possibilities can reduce the overall DG neurogenesis during chronic epilepsy. From the above, it is clear that currently there is no consensus regarding reductions in the number of NSCs during chronic epilepsy. A rat study suggests ∼30% depletion in the number, whereas a human study implies no such reductions (Shetty, personal communication; Crespel et al., 2005). Yet, from both studies, it emerges that substantial numbers of NSCs persist in the SGZ of the chronically epileptic hippocampus (Fig. 2). Persistence of NSCs during chronic epilepsy is encouraging for employing strategies that have the ability to induce neuronal differentiation in newly born cells derived from NSCs.

Changes in the hippocampal microenvironment

It is well known from multiple studies that higher concentrations of neurotrophic factors such as epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) can enhance DG neurogenesis (Cheng et al., 2001; Lichtenwalner et al., 2001; Jin et al., 2002a, 2002b; Yoshimura et al., 2003; Rai et al., 2007). Consistent with this idea, increased neurogenesis observed shortly after SE or brain injury has been found to be associated with the upregulation of these factors. However, chronic epilepsy has been found to be associated with reduced concentration of many of these factors (Fig. 2). These include FGF-2, IGF-1, and BDNF (Shetty et al., 2003; Hattiangady et al., 2004). The chronically epileptic hippocampus exhibited 75% less FGF-2, 53% less IGF-1, and 64% less BDNF than intact hippocampus (Shetty et al., 2003; Hattiangady et al., 2004). In addition to these, several other factors that are important for DG neurogenesis may decrease during chronic epilepsy. Indeed, a preliminary study shows decreased expression of GDNF during chronic epilepsy (Shetty, personal communication). Because GDNF exhibits both neurogenesis-promoting effects (Chen et al., 2005; Kobayashi et al., 2006) and anticonvulsant properties (Kanter-Schlifke et al., 2007), decreased GDNF may contribute to both diminished neurogenesis and increased frequency of SRMS during chronic epilepsy. Furthermore, an inhibitor of the wingless-type murine mammary tumor virus (MMTV) integration site family protein (Wnt) Dickkopf-1 is elevated in mesial TLE (Busceti et al., 2007). This may also contribute to decreased DG neurogenesis during chronic epilepsy because overexpression of Wnt3 increases neurogenesis in hippocampal NSCs and blockade of Wnt signaling abolishes DG neurogenesis (Lie et al., 2005).

However, VEGF expression in a variety of hippocampal cells was found to increase during chronic epilepsy in both humans and animal models (Rigau et al., 2007). Increased VEGF expression was also associated with increased angiogenic processes and disruption of the blood–brain barrier (Rigau et al., 2007). It is possible that increased VEGF levels maintain the proliferation of NSCs during chronic epilepsy at levels observed in age-matched intact hippocampus (Hattiangady et al., 2005a). This is because VEGF is considered as one of the important mitogenic factors for NSCs. On the other hand, decreased levels of BDNF, IGF-1, FGF-2, GDNF, and Wnt proteins likely dampen the neuronal differentiation of newly born cells. Thus, considerable changes occur in the microenvironment of the hippocampus in chronic epilepsy that likely influence the overall decline in DG neurogenesis.

Chronic inflammation

Hippocampal inflammation commonly observed after injury can considerably suppress DG neurogenesis (Crespel et al., 2002; Ekdahl et al., 2003; Monje et al., 2003). Inflammation persists during the chronic phase of epilepsy, though it is considerably less than that observed shortly after SE (Crespel et al., 2002; Hattiangady et al., 2004; Bonde et al., 2006). A study examining the hippocampi from patients with mesial TLE and hippocampal sclerosis reports association of neuronal loss with considerable gliosis in both CA1 and CA3 subfields (Crespel et al., 2002). Dual immunolabeling analyses revealed overexpression of nuclear factor (NF) kappaB-p65 in reactive astrocytes occupying lesioned areas, suggesting that inflammatory processes are chronically active or transiently reinduced by recurrent seizures in the epileptic hippocampus with sclerosis (Crespel et al., 2002). However, evaluation of activated microglial cells in the chronically epileptic hippocampus at 5 months after the initial KA-induced injury in a rat model of TLE demonstrated considerably reduced density of activated microglial cells, in comparison to their density at 2 weeks after KA-induced injury (Hattiangady et al., 2004). Thus, in the KA model, increased inflammation was seen when neurogenesis was dramatically upregulated, and reduced inflammation was observed when neurogenesis was radically decreased. These results underscore that chronic inflammation is not the major reason underlying decreased neurogenesis in chronic epilepsy. However, some contribution from the persisting activated microglial cells toward reduced neurogenesis cannot be ruled out.

Granule cell dispersion

Granule cell dispersion (GCD) is a characteristic feature observed in ∼40% cases of TLE with hippocampal sclerosis and in some animal models of TLE (Houser, 1990; Harding & Thom, 2001; Kralic et al., 2005; Fahrner et al., 2007). A recent study implies that GCD is caused by the displacement of mature granule cells due to a deficiency in reelin (Heinrich et al., 2006; see review by Parent and Murphy this issue). It has also been suggested that seizure-induced increase in DG neurogenesis (during the early phase after an IPI) does not contribute to GCD as the occurrence of GCD was found to be associated with a progressive decline and absence of DG neurogenesis (Heinrich et al., 2006; Fahrner et al., 2007). However, it is also unlikely that GCD causes the decline in DG neurogenesis as decreased DG neurogenesis in animals exhibiting chronic epilepsy has been consistently observed in the absence of GCD (Hattiangady et al., 2004, 2005a). Thus, GCD is another pathology observed in a fraction of TLE cases with hippocampal sclerosis. Although GCD is associated with decreased DG neurogenesis, currently there is no evidence to support that GCD induces decreased neurogenesis in animals exhibiting chronic epilepsy or in human TLE.

Changes in reelin and cystatin C

Reelin is an extracellular matrix protein essential for the proper migration of neurons. Recent studies have suggested a link between DG neurogenesis and reelin expression. First, a study demonstrates reduced neurogenesis with preferential differentiation of newly born cells into astrocytes in mice lacking reelin, also called the reeler mice (Zhao et al., 2007). Second, reduced reelin expression has been observed after the pilocarpine-induced SE in rats, which appeared to induce ectopic chain migration and aberrant integration of newborn dentate granule cells (Gong et al., 2007). Thus, it is possible that reelin deficiency observed during chronic epilepsy (Heinrich et al., 2006) contributes to decreased neurogenesis and aberrant migration of newly born neurons into the dentate hilus. Cystatin C, a protease inhibitor, is another factor that is upregulated during chronic epilepsy (Pirttila et al., 2005a, 2005b). In patients with TLE, higher level of cystatin C expression was associated with decreased neurogenesis. However, the extent of aberrant migration of newly born neurons was enhanced, implying that increased cystatin C levels might be promoting the abnormal migration of newly born neurons. Thus, simultaneous downregulation of reelin and upregulation of cystatin C may contribute to both decreased DG neurogenesis and abnormal migration of newly born neurons during chronic epilepsy.

Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

Diminished DG neurogenesis in chronic epilepsy might contribute to the persistence of spontaneous seizures, learning and memory impairments, and depression seen in epileptic patients as well as in animal models of TLE (Fig. 2). The potential links between DG neurogenesis and each of the above pathophysiological alterations are discussed in the following sections.

Dentate hyperexcitability and spontaneous seizures

There is no direct evidence to support that diminished neurogenesis plays a role in the maintenance of SRMS during chronic epilepsy. However, a study suggests that ∼14% of newly born neurons in the DG of young rats differentiate into inhibitory GABAergic basket cells (Liu et al., 2003). If this scenario were also true in diseased conditions, dramatically decreased DG neurogenesis during chronic epilepsy would result in minimal addition of new GABAergic basket cells into the DG circuitry. This may contribute to the persistence of reduced inhibitory neurotransmission and exacerbation of dentate hyperexcitability with time. Studies in animal models of TLE suggest both reduced inhibition of granule cells and reduced number of GABAergic basket cells in the DG during chronic epilepsy (Shetty & Turner, 2001; Kobayashi & Buckmaster, 2003; Morimoto et al., 2004). Nevertheless, it remains to be established whether these changes in inhibitory transmission occur because of decreased addition of new GABA-ergic cells through neurogenesis or simply through the loss of existing GABAergic interneurons over time. Another study, using an electrical stimulation model of SE, suggests that granule cells that are born and integrated into the GCL at extended time points after SE integrate in such a way that they receive reduced excitatory synaptic input and exhibit an enhanced inhibitory synaptic drive (Jakubs et al., 2006). These results imply that functional integration of neurons born in pathological conditions is adjusted to the prevailing functional state in the pathological hippocampal network (Jakubs et al., 2006; Kempermann, 2006). Considering this, it is possible that decreased addition of new neurons into the GCL interferes with the possible spontaneous repair of hyperexcitability in the DG. Thus, in conditions such as chronic epilepsy, where the neural circuitry is already proexcitatory, substantially declined neurogenesis may contribute to the maintenance and/or exacerbation of DG hyperexcitability. However, it should be noted that the pattern of integration of new granule cells reported by Jakubs et al. (2006) does not seem to happen in the chemoconvulsant (KA or pilocarpine) models of TLE. This is because, in these models, decreased DG neurogenesis during chronic epilepsy is associated with aberrant migration of considerable fractions of newly born neurons into the dentate hilus (Hattiangady et al., 2004). Additionally, new granule cells that integrate into the SGZ-GCL in these models demonstrate an increased occurrence of basal dendrites (Shapiro & Ribak, 2006; Jessberger et al., 2007; Walter et al., 2007), a feature known to promote aberrant synaptic reorganization in the epileptic hippocampus.

Learning and memory function

It is hypothesized that the maintenance of hippocampal-dependent learning and formation of the temporal clusters of long-term episodic memories require continuous addition of newly functional granule cells into the GCL circuitry (Shors et al., 2002; van Praag et al., 2002; Jessberger & Kempermann, 2003; Kempermann et al., 2004; Aimone et al., 2006; Kee et al., 2007). From this perspective, decreased addition of new functional granule cells into the GCL during chronic epilepsy would likely impair the hippocampal-dependent learning and memory function and culminate in cognitive deficits associated with chronic TLE (Fig. 2). Indeed, clinical studies report that patients with a longer duration of refractory TLE exhibit more severe cognitive impairments (Jokeit & Ebner, 1999; Brown-Croyts et al., 2000; Alessio et al., 2004). Thus, it is possible that cognitive deterioration observed in patients with refractory TLE is at least partially linked to diminished DG neurogenesis. However, a cause–effect relationship between decreased neurogenesis and cognitive impairments during chronic TLE remains to be established in future studies. If the potential linkage turns out be true, strategies that are efficacious for enhancing DG neurogenesis during chronic epileptic conditions will be therapeutic. Nevertheless, it should be noted that KA administration or other brain insults lead to persistent loss of significant fractions of several hippocampal cell types in addition to decreased neurogenesis, which may also affect the learning ability.

Depression

Many studies have suggested a role for hippocampal neurogenesis in mediating some of the behavioral effects of antidepressants (Sahay et al., 2007). Animal studies show that disruption of the antidepressant-induced neurogenesis blocks behavioral improvements mediated by antidepressants (Santarelli et al., 2003; Drew & Hen, 2007; Sahay & Hen, 2007). It has been suggested that reversal of the decreased neurogenesis is one way by which antidepressant drugs exert their positive effects (Malberg, 2004). Thus, reduced DG neurogenesis might contribute to the pathophysiology of depression observed in patients with chronic epilepsy. In this context, development of strategies that enhance the production of new neurons in the chronically epileptic hippocampus may be useful for alleviating depression in epileptic patients.

Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

From the analyses of DG neurogenesis in animals exhibiting chronic epilepsy, it emerges that the microenvironment that supports the production and the long-term survival of newly born cells is mostly unchanged with chronic epilepsy (Hattiangady et al., 2005a; Fig. 2). However, the microenvironment that promotes neuronal differentiation of newly generated cells is altered considerably during chronic epilepsy (Hattiangady et al., 2005a; Kralic et al., 2005). This might involve decreased concentration of critical factors such as the BDNF, GDNF, FGF-2, IGF-1, and Wnt3 protein during chronic epilepsy. Therefore, development of strategies that enhance the concentration of these factors as well as other proteins that enhance neuronal differentiation of newly born cells are needed for enhancing DG neurogenesis in the chronically epileptic hippocampus.

Grafting of stem cells

Grafting of stem cells into the hippocampus may be beneficial for improving neurogenesis during chronic epilepsy. A recent study demonstrates that grafting of NSCs or glial progenitors is efficacious for improving neurogenesis in the aging rat hippocampus (Hattiangady et al., 2007). The precise mechanisms by which this approach increased neurogenesis from endogenous NSCs were unclear. However, it appeared to be mediated through increased concentration of neurotrophic factors such as FGF-2, BDNF, and IGF-1 as both NSCs and glial progenitors exhibited robust expression of these factors (Hattiangady et al., 2007). As both decreased neurogenesis and reduced concentration of multiple neurotrophic factors that support hippocampal neurogenesis observed in chronic epilepsy also occur during aging (Kuhn et al., 1996; Hattiangady et al., 2005b; Rao et al., 2005; Shetty et al., 2005b; Rao et al., 2006b), grafting of NSCs or glial progenitors appears to be a promising approach for improving neurogenesis in the chronically epileptic hippocampus. Grafting of stem cells into the chronically epileptic hippocampus may also induce other beneficial effects such as seizure control and improved learning and memory (Shetty & Hattiangady, 2007b). For example, if grafted stem cells generate significant numbers of GABAergic interneurons (as observed when they were grafted early after SE, Chu et al., 2004), this may lead to decreased frequency and intensity of SRMS through connectivity of these newly generated interneurons with the host neurons exhibiting increased excitability. Alternatively, grafted stem cells may induce antiseizure effects through secretion of anticonvulsant factors. Thus, stem cell grafting approach for chronic TLE has considerable promise. However, rigorous studies using animal models of chronic TLE are needed in future to comprehend the behavior, differentiation, integration, and neurotrophic activity of grafted NSCs. These studies also need to ascertain the possible long-term efficacy of this approach for restraining seizures, improving DG neurogenesis, reversing learning and memory dysfunction, and alleviating depression.

Administration of neurotrophic factors

Chronic epilepsy is associated with reduced levels of several neurotrophic factors that are considered as positive regulators of DG neurogenesis in the hippocampus that include FGF-2, IGF-1, and BDNF (Shetty et al., 2003; Hattiangady et al., 2004). Therefore, it is possible that dramatically declined neurogenesis during chronic epilepsy is a result of decreased levels of these neurotrophic factors. From this perspective, administration of these factors (either individually or in combination) may stimulate increased neurogenesis from endogenous NSCs that persist in the chronically epileptic hippocampus. Although no studies are available on the effects of administration of these factors into the chronically epileptic hippocampus, studies in other models strongly support their use for improving neurogenesis. These include increased neurogenesis observed in the aging hippocampus following intracerebroventricular administration of IGF-1 (Lichtenwalner et al., 2001) and FGF-2 (Jin et al., 2003; Rai et al., 2007) using osmotic minipumps. Furthermore, as the blood–brain barrier is leaky during chronic epilepsy, likely because of increased VEGF expression and angiogenic processes, these neurotrophic factors may be delivered through either subcutaneous or systemic injections. If successful, this will avoid the invasive approach of delivering factors through cannula implantation into the brain and prevent the possible brain infections linked to the procedure. Although the effects of subcutaneous administration of neurotrophic factors during chronic epilepsy have not been examined so far, subcutaneous administration of FGF-2 and/or BDNF was found to be efficacious for greatly improving neurogenesis in the injured aged hippocampus (Shetty, personal communication). Thus, administration of neurotrophic factors during chronic epilepsy has promise for improving DG neurogenesis.

Physical exercise

Physical exercise may be useful for improving neurogenesis during chronic epilepsy. It is well known that physical exercise induces beneficial effects on overall health and cognitive functions (Cotman et al., 2007). In the hippocampus, physical activity considerably increases neurogenesis through an enhanced proliferation of NSCs and increased neuronal differentiation of newly born cells (van Praag et al., 1999; Kempermann et al., 2000; van Praag et al., 2005). Voluntary running exercise from 3 to 9 months of age in mice can maintain DG neurogenesis to levels typically observed in younger animals (Kronenberg et al., 2006). A moderate exercise has also been shown to be useful for enhancing DG neurogenesis and learning and memory function in rats with hippocampal injury (Chen et al., 2006). A recent study shows that exposure to voluntary wheel running after stroke enhances survival of newborn cells, upregulates the phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB) in the DG, and reverses the ischemia-induced spatial memory impairments (Luo et al., 2007). It also emerges that voluntary exercise increases the levels of BDNF, NGF, VEGF, and other growth factors that stimulate neurogenesis and improves cognitive function (Neeper et al., 1995; Neeper et al., 1996; Fabel et al., 2003; Soya et al., 2007). Considering these, moderate physical exercise during chronic epilepsy appears to be beneficial for improving neurogenesis. This may also have some positive effects on the frequency and intensity of SRMS. Indeed, clinical studies suggest that physical exercise decreases the frequency and severity of seizures (Denio et al., 1989; Eriksen et al., 1994). Studies in animal models are also supportive of the beneficial effects of physical exercise on epilepsy. Physical exercise retards the development of kindling (Arida et al., 1998). Furthermore, in a pilocarpine model of epilepsy, physical exercise diminishes the frequency of seizures (Arida et al., 1999), reduces the hyperresponsiveness of CA1 pyramidal neurons and increases the magnitude of hippocampal long-term potentiation (Arida et al., 2004), and preserves a substantial fraction of hippocampal parvalbumin immunopositive interneurons (Arida et al., 2007). Another study suggests that physical exercise improves learning after KA-induced hippocampal neurodegeneration (Gobbo & O'Mara, 2005). Thus, physical exercise has promise for increasing neurogenesis, reducing seizures, and improving cognitive function during chronic epilepsy. Long-term studies are, however, required to assess the extent of improvements with this approach.

Exposure to enriched environment

Exposure to enriched environment is an attractive approach for inducing robust neuronal plasticity in both intact and injured brain (Nithianantharajah & Hannan, 2006), and may be useful for enhancing neurogenesis in the chronically epileptic hippocampus. Environmental enrichment typically consists of many components, such as expanded learning opportunities, increased social interaction and physical activity, and larger housing (Nithianantharajah & Hannan, 2006). The plasticity mediated by environmental enrichment includes multiple morphological, physiological, neurochemical, and cognitive changes. The morphological changes include increases in the brain weight Bennett et al., 1969; Henderson, 1970), cerebral cortex thickness (Greer et al., 1981), dendritic growth and spine number (Johansson & Belichenko, 2002; Leggio et al., 2005), and synapses (Foster et al., 1996; Mora et al., 2007). The physiological changes comprise enhanced synaptic strength (Foster & Dumas, 2001) and increased excitatory glutamatergic synaptic transmission (Nichols et al., 2007). The neurochemical changes involve increased concentration of neurotrophic factors such as GDNF (Young et al., 1999), neurotrophins BDNF, NGF, and NT-3 (Ickes et al., 2000; Zhu et al., 2006), and VEGF (During & Cao, 2006). Alterations in cognitive function include enhanced long-term potentiation (Duffy et al., 2001; Tang & Zou, 2002) and improved spatial learning and memory performance (Kempermann et al., 1997; Moser et al., 1997; Pham et al., 2002; Huang et al., 2007). Moreover, several studies have shown that exposure to enriched environment increases DG neurogenesis (Kempermann et al., 1997; Olson et al., 2006). Furthermore, a link between increased DG neurogenesis and improved functional outcome in animals exposed to an enriched environment has been suggested in models of aging (Kempermann et al., 2002), traumatic brain injury (Gaulke et al., 2005), Huntington's and Alzheimer's diseases (Lazic et al., 2006; Levi & Michaelson, 2007), and cranial irradiation (Fan et al., 2007).

Pertaining to epilepsy and enrichment, a study has shown that preenrichment in adult rats increases the seizure threshold and decreases hippocampal neurodegeneration when challenged with KA (Young et al., 1999; Auvergne et al., 2002). Furthermore, housing animals in environmentally enriched conditions after the induction of SE improves learning and memory abilities and minimizes the probability of developing behavioral abnormalities and depression in immature rats (Faverjon et al., 2002; Rutten et al., 2002; Koh et al., 2005, 2007). Interestingly, immature rats that underwent SE and were housed in enriched environment exhibited increases in DG neurogenesis and phosphorylation of CREB (Faverjon et al., 2002). Thus, several beneficial effects of enrichment have been demonstrated in epilepsy models. However, hitherto, no studies that examine the effects of environmental enrichment on DG neurogenesis or the frequency and intensity of SRMS during chronic epilepsy are available.

Antidepressant therapy

It is now well known that virtually all antidepressant treatments enhance DG neurogenesis (Santarelli et al., 2003; Malberg, 2004; Drew & Hen, 2007; Perera et al., 2007). A greatly enhanced DG neurogenesis following chronic antidepressant treatment is likely mediated by increased: (1) concentrations of serotonin and/or norepinephrine (Duman et al., 1997; Carlezon et al., 2005); (2) cAMP–CREB cascade (Nestler et al., 1989; Nibuya et al., 1996; Thome et al., 2000); and (3) levels of BDNF, VEGF, FGF-2, and IGF-1 (Fabel et al., 2003; Khawaja et al., 2004). Pertaining to the link between DG neurogenesis and depression, a study demonstrates that the disruption of the antidepressant-induced neurogenesis blocks the positive behavioral responses mediated by antidepressants (Santarelli et al., 2003). However, it is not clear whether decreased DG neurogenesis is one of the characteristic pathophysiological features of depression. Thus, from the studies conducted so far, it appears that though depression is not caused by decreased DG neurogenesis, clinical improvements through antidepressant therapy are mediated through increased DG neurogenesis (Drew & Hen, 2007; Sahay & Hen, 2007). As decreased DG neurogenesis, learning and memory impairments, and depression coexist during chronic epilepsy, prolonged antidepressant therapy may be useful. Rigorous studies in animal models of chronic TLE examining all three issues are needed in future studies.

Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

The idea of increasing DG neurogenesis during chronic epilepsy using a variety of strategies described above is appealing, considering the possible involvement of DG neurogenesis in hippocampal-dependent learning and memory function and mood, and because learning and memory impairments and depression are comorbidities in chronic epilepsy. However, it is difficult to predict the overall effects of increased DG neurogenesis during chronic epilepsy on the frequency and intensity of SRMS because of the suggested role of abnormal DG neurogenesis occurring at early time points after SE toward the development of chronic epilepsy. It has been shown that new granule cells that migrate into the dentate hilus during the early phase after SE get incorporated aberrantly into the CA3 network (Scharfman et al., 2000) and establish afferent connectivity with mossy fiber terminals (Pierce et al., 2005). This pattern of incorporation has been suggested to predispose the ectopic granule cells for generating epileptiform bursts. This suggestion is based on observations that the ectopic granule cells exhibit: (1) activation when epileptic rats are having SRMS (Scharfman et al., 2002; Jessberger et al., 2007); (2) a longer latency to onset of evoked responses with perforant path stimulation (Scharfman et al., 2003); and (3) spontaneous bursts of action potentials (Scharfman et al., 2000). Additional studies imply that these ectopic granule cells contribute to SRMS in chronically epileptic animals (Jung et al., 2004; McCloskey et al., 2006).

Thus, the outcome of increased DG neurogenesis during chronic epilepsy will depend upon the behavior and connectivity of newly born neurons. If a vast majority of newly born neurons in the SGZ migrate into the GCL and incorporate into the hippocampal circuitry with appropriate afferent and efferent connectivity or with a pattern of connectivity described by Jakubs et al. (2007), this may have beneficial effects in terms of restraining SRMS and alleviating learning and memory impairments and depression. On the other hand, if a major fraction of newly born neurons exhibit aberrant migration and incorporate inappropriately in the dentate hilus or the molecular layer, this would exacerbate the epileptogenic circuitry in the chronically epileptic hippocampus. Instead of restraining seizures, it may increase the frequency and intensity of seizures. Such haphazard DG neurogenesis may also worsen learning and memory function and depression. Thus, detailed studies examining the links among increased DG neurogenesis, frequency and intensity of SRMS, learning and memory function, and depression in chronic epileptic conditions are clearly required. This would determine whether increasing neurogenesis through distinct strategies is appropriate for easing various impairments linked to chronic TLE.

Acknowledgments

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References

This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS054780 & NS 043507 to A.K.S.), National Institute for Aging (AG20924 to A.K.S.), and the Department of Veterans Affairs (VA Merit Review Award to A.K.S.).

Conflict of interest: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The contributing authors to this article have declared no conflicts of interest.

References

  1. Top of page
  2. Extent of Dentate Neurogenesis in Chronic TLE
  3. Mechanisms of Radically Declined Dentate Neurogenesis in Chronic TLE
  4. Potential Repercussions of Decreased DG Neurogenesis in Chronic TLE
  5. Prospective Strategies for Augmenting Dentate Neurogenesis in Chronic TLE
  6. Possible Ramifications of Increasing Dentate Neurogenesis in Chronic TLE
  7. Acknowledgments
  8. References