Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies

Ample evidence points to the dentate gyrus as anatomical region for persistent neurogenesis in the adult mammalian brain. This has been confirmed in a variety of animal models under physiological as well as pathophysiological conditions. Notwithstanding, similar experiments are difficult to perform in humans. Postmortem studies demonstrated persisting neurogenesis in the elderly human brain. In addition, neural precursor cells can be isolated from surgical specimens obtained from patients with intractable temporal lobe epilepsy (TLE) and propagated or differentiated into neuronal and glial lineages. It remains a controversial issue, whether epileptic seizures have an effect on or even increase hippocampal neurogenesis in humans. Recent data support the notion that seizures induce neurogenesis in young patients, whereas the capacity of neuronal recruitment and proliferation decreases with age. Animal models of TLE further indicate that these newly generated neurons integrate into epileptogenic networks and contribute to increased seizure susceptibility. However, pathomorphological disturbances within the epileptic hippocampus, such as granule cell dispersion (GCD), may not directly result from compromised neurogenesis. Still, the majority of adult TLE patients present with significant dentate granule cell loss at an end stage of the disease, which relates to severe memory and learning disabilities. In conclusion, surgical specimens obtained from TLE patients represent an important tool to study mechanisms of stem cell recruitment, proliferation and differentiation in the human brain. In addition, increasing availability of surgical specimens opens new avenues to systematically explore disease pathomechanisms in chronic epilepsies.     

Increased leak conductance in dentate gyrus granule cells of temporal lobe epilepsy patients with Ammon's horn sclerosis

Purpose:   Temporal lobe epilepsy (TLE) is often associated with Ammon's horn sclerosis (AHS) characterized by hippocampal cell death and dentate gyrus granule cell dispersion (GCD). Granule cells survive AHS and have been proposed to be hyperexcitable in TLE. Here we studied whether the passive excitability of granule cells correlates with the severity of AHS.
Methods:   We analyzed the passive membrane properties of identified granule cells using patch-clamp recordings in acute tissue slices obtained from TLE surgery. Independent Wyler grading and GCD measurements were used to assess the severity of AHS.
Results:   The input resistances and membrane time constants of granule cells were reduced in high-grade versus low-grade AHS samples and negatively correlated with the degree of GCD. Granule cells possessed large Ba²⁺-sensitive, inwardly rectifying K⁺ conductances.
Discussion:   The increased leak conductance, likely mediated by K⁺ channels, does not argue for an increased excitability of granule cells but rather points to a neuroprotective mechanism in the sclerotic focus in TLE.     

Cystatin C expression is associated with granule cell dispersion in epilepsy

Human temporal lobe epilepsy (TLE) is associated with cellular alterations (eg, hilar cell death, neurogenesis, and granule cell dispersion) in the dentate gyrus but their underlying molecular mechanism are not known. We previously demonstrated increased expression of cystatin C, a protease inhibitor linked to both neurodegeneration and neurogenesis, during epileptogenesis in the rat hippocampus. Here, we investigated cystatin C expression in the dentate gyrus in chronic epilepsy and its association with neuronal loss and neurogenesis. In both rats with epilepsy and human patients with TLE, cystatin C expression was increased in glial cells in the molecular layer of the dentate gyrus, being most prominent in cases with granule cell dispersion. In patients with TLE, high cystatin C expression associated with greater numbers of polysialylated neural cell adhesion molecule-positive newborn cells in the molecular layer, although the overall number was decreased, indicating that the newborn cells migrate to abnormal locations in the epileptic dentate gyrus. These data thus demonstrate that cystatin C expression is altered during the chronic phase of epilepsy and suggest that cystatin C plays a role in network reorganization in the epileptic dentate gyrus, especially in granule cell dispersion and guidance of migrating newborn granule cells.     

Balance between neurogenesis and gliogenesis in the adult hippocampus: role for reelin

The extracellular matrix protein reelin is essential for the proper radial migration of cortical neurons. In reeler mice lacking reelin, there is a malformation of the radial glial scaffold required for granule cell migration. Immunostaining for glial fibrillary acidic protein (GFAP) reveals abundant radial glial cells with long fibers traversing the granular layer in the wild type, but almost exclusively astrocytes in the reeler mutant. With the concept that radial glial cells are precursors of neurons, we hypothesized that the balance between neurogenesis and gliogenesis is altered in the reeler mutant. To this end, adult reeler mutants and their wild-type littermates were injected with bromodeoxyuridine (BrdU), a marker of newly generated cells. When compared to wild-type animals, we found a reduction in the number of BrdU-labeled cells in the adult reeler dentate gyrus. Moreover, whereas there was a dramatic decrease in the number of newly generated granule cells identified by double labeling for BrdU and NeuN, the number of BrdU-labeled, GFAP-positive astrocytes had increased. Decreased neurogenesis in the adult reeler dentate gyrus was confirmed by immunostaining for doublecortin, a marker of newly generated neurons. These results indicate that adult neurogenesis is altered in the reeler dentate gyrus and that newly generated cells preferentially differentiate into astrocytes.     

Exogenous reelin prevents granule cell dispersion in experimental epilepsy

Temporal lobe epilepsy (TLE) is often accompanied by granule cell dispersion (GCD), a migration defect of granule cells in the dentate gyrus. We have previously shown that a decrease in the expression of reelin, an extracellular matrix protein important for neuronal positioning, is associated with the development of GCD in TLE patients. Here, we used unilateral intrahippocampal injection of kainate (KA) in adult mice which is also associated with GCD formation and a decrease of reelin expression. In this mouse epilepsy model we aimed to prevent GCD development by the application of exogenous reelin. As a prerequisite we analyzed whether the reelin signaling transduction cascade was preserved in the KA-injected hippocampus. Using in situ hybridization and Western blot analysis we found that the expression of the reelin signaling components, apolipoprotein E receptor 2, the very-low-density lipoprotein receptor and the intracellular adaptor protein disabled 1, was maintained in dentate granule cells after KA injection. Next, recombinant reelin was infused into the KA-injected hippocampus by osmotic minipumps over a period of 2 weeks. Quantitative analysis of granule cell layer width revealed a significant reduction of GCD in reelin-treated, but not in saline-infused animals when compared to KA injection alone. Our findings highlight the crucial role of reelin for the maintenance of granule cell lamination in the dentate gyrus of adult mice and show that a reelin deficiency is causally involved in GCD development.     

Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures

Adult hippocampal neurogenesis is enhanced in response to multiple stimuli including seizures. However, the relationship between neurogenesis and the development of temporal lobe epilepsy (TLE) remains unclear. Unilateral intrahippocampal injection of kainate in adult mice models the morphological characteristics (e.g. neuronal loss, gliosis, granule cell dispersion and hypertrophy) and occurrence of chronic, spontaneous recurrent partial seizures observed in human TLE. We investigated the influence of a kainate-induced epileptogenic focus on hippocampal neurogenesis, comparing neural stem cell proliferation following status epilepticus and spontaneous recurrent partial seizures. Cell proliferation in the subgranular zone was transiently increased bilaterally after kainate treatment. As a result, neurogenesis was stimulated in the contralateral dentate gyrus. In contrast, the epileptic hippocampus exhibited a strongly reduced neurogenic potential, even after onset of spontaneous recurrent partial seizures, possibly due to an alteration of the neurogenic niche in the subgranular zone. These results show that neurogenesis does not contribute to the formation of the epileptic focus and may be affected when dispersion of dentate gyrus granule cells occurs. Therefore, in patients with TLE, hippocampal sclerosis and granule cell dispersion may play a significant role in disrupting the potential for hippocampal neurogenesis.     

Granule cell dispersion and aberrant neurogenesis in the adult hippocampus of an LIS1 mutant mouse

Human type 1 lissencephaly is a severe brain malformation associated with cognitive dysfunction and intractable epilepsy. Mutant mice with a heterozygous deletion of LIS1 show varying degrees of hippocampal abnormality and enhanced excitability. Whether a reduction of LIS1 function affects adult hippocampal neurogenesis, and if so, whether aberrant neurogenesis contributes to the generation of a disorganized hippocampus remain unknown. Previous reports indicate the presence of multiple pyramidal cell layers and granule cell dispersion in LIS1 mutant mice. Here we observed disruption of the subgranular zone and glial fibrillary acidic protein-immunoreactive radial astrocytes in the dentate gyrus of adult LIS1 mice. Using pulse-chase bromodeoxyuridine (BrdU) labeling combined with neuronal and glial antibody staining we provide evidence for ectopic adult neurogenesis in LIS1 mice. A gradually decreased survival rate for these newborn granule cells was also demonstrated in LIS1 mice 7 days after BrdU injection. This reduced survival rate was associated with impaired neuronal differentiation 28 days after BrdU administration. Thus, LIS1 haploinsufficiency can lead to abnormal cell proliferation, migration and differentiation in the adult dentate gyrus.     

Limbic P300s in temporal lobe epilepsy with and without Ammon's horn sclerosis.

Limbic P300 potentials can be recorded within the mesial temporal lobes of patients with temporal lobe epilepsy (TLE). To delineate possible mechanisms of their generation and pathological alteration, we analysed limbic P300s in 55 TLE patients with and 29 without Ammon's horn sclerosis (AHS) and correlated their amplitudes with neuronal cell counts in 30 histopathological specimens. Limbic P300 amplitudes were reduced on the side of the epileptogenic focus only in patients with AHS. Moreover, in AHS patients, limbic P300 latencies were prolonged bilaterally; and in patients with left-sided AHS, amplitudes were reduced bilaterally. Both findings suggest bilateral functional deficits in TLE with unilateral AHS. Limbic P300 areas correlated significantly with neuronal densities of dentate gyrus granule cells but not hippocampal pyramidal cells in the CA1-4 (cornu ammonis) subfields. This finding points to a potential mechanism for the bilateral effects of unilateral AHS as both dentate gyri exhibit strong reciprocal contralateral connectivity.     

Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.

A considerable potential for neurogenesis has been identified in the epileptic rat hippocampus. Here, we explore this feature in human patients suffering from chronic mesial temporal lobe epilepsy. Immunohistochemical detection of the neurodevelopmental antigen nestin was used to detect neural precursor cells, and cell-type specific markers were employed to study their histogenetic origin and potential for neuronal or glial differentiation. The ontogenetic regulation of nestin-positive precursors was established in human control brains (week 19 of gestation-15 years of age). A striking increase of nestin-immunoreactive cells within the hilus and dentate gyrus could be observed in a group of young patients with temporal lobe epilepsy (TLE) and surgical treatment before age 2 years compared to adult TLE patients and controls. The cellular morphology and regional distribution closely resembled nestin-immunoreactive granule-cell progenitors transiently expressed during prenatal human hippocampus development. An increased Ki-67 proliferation index and clusters of supragranular nestin-immunoreactive cells within the molecular layer of the dentate gyrus were also noted in the group of young TLE patients. Confocal studies revealed colocalization of nestin and the betaIII isoform of tubulin, indicating a neuronal fate for some of these cells. Vimentin was consistently expressed in nestin-immunoreactive cells, whereas cell lineage-specific markers, i.e., glial fibrillary acidic protein, MAP2, neurofilament protein, NeuN, or calbindin D-28k failed to colocalize. These findings provide evidence for increased neurogenesis in pediatric patients with early onset of temporal lobe epilepsy and/or point towards a delay in hippocampal maturation in a subgroup of patients with TLE.     

Could hippocampal neurogenesis be a future drug target for treating temporal lobe epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.     

Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis.

BACKGROUND: Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus. Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat. METHODS: Animals were injected with agomelatine for different time periods. Immunostaining for bromodeoxyuridine, neuron specific nuclear protein, and glial fibrillary acid protein, as well as for the highly polysialylated form of neuronal cell adhesion molecule and doublecortin, was used to detect changes in cell proliferation, neurogenesis, and survival. Cell death was estimated by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling and cresyl violet staining. RESULTS: Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant-anxiolytic properties of the drug. Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus. Finally, agomelatine treatment does not affect mature granule cells. CONCLUSIONS: This study shows that an antidepressant can affect differentially various stages of neurogenesis in the dorsal and ventral hippocampus. Altogether, these changes lead to a pronounced augmentation in the total number of new granule cells.     

Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy

M. Paradisi, M. Fernández, G. Del Vecchio, G. Lizzo, G. Marucci, M. Giulioni, E. Pozzati, T. Antonelli, G. Lanzoni, G. P. Bagnara, L. Giardino and L. Calzà (2010) Neuropathology and Applied Neurobiology 36, 535–550
Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy Aims: Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero‐mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. Methods: Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT‐PCR in neurospheres. Results: We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain‐derived neurotrophic factor, ciliary neurotrophic factor, glial‐derived neurotrophic factor, nerve growth factor). Conclusion: We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS.     

Properties of a Delayed Rectifier Potassium Current in Dentate Granule Cells Isolated from the Hippocampus of Patients with Chronic Temporal Lobe Epilepsy

Summary: Purpose: Properties of potassium outward currents were investigated in human hippocampal dentate gyrus granule cells from 11 hippocampal specimens obtained from patients with temporal lobe epilepsy (TLE) during resective surgery. Methods: Dentate granule cells were isolated enzymatically and outward currents analyzed by using the whole-cell configuration of the patch-clamp method. Hippocampal specimens were classified neuropathologically with respect to severe segmental cell loss, gliosis, and axonal sprouting (Ammon's horn sclerosis, AHS), or the presence of a focal lesion in the adjacent temporal lobe. Results: A delayed rectifier outward current (I), but not an A-type potassium current (I_k) or inwardly rectifying potassium currents, was observed in all cells. The average current density of I_k, the time-dependent decay of I_k, and the resting membrane characteristics were not significantly different between patients with and without AHS. The voltage of half-maximal activation V_1/2(act) was 5·4 ± 1·8 mV in AHS compared with ?2·9 ± 1·8 mV in lesion-associated epilepsy (NS). In contrast, V_1/2(inact) was shifted in a hyperpolarizing direction in AHS (?67·7 ± 0·6 mV) compared with that in hippocampi not showing AHS (?47·7 ± 2·6 mV; p = 0·0017). Conclusions: The altered steady-state voltage-dependence of I_k, may result in abnormal excitability of dentate granule cells in AHS and exert a marked influence on input-output properties of the dentate gyrus.     

Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gyrus

The dentate gyrus is one of only two regions of the mammalian brain where substantial neurogenesis occurs postnatally. However, detailed quantitative information about the postnatal structural maturation of the primate dentate gyrus is meager. We performed design‐based, stereological studies of neuron number and size, and volume of the dentate gyrus layers in rhesus macaque monkeys (Macaca mulatta) of different postnatal ages. We found that about 40% of the total number of granule cells observed in mature 5–10‐year‐old macaque monkeys are added to the granule cell layer postnatally; 25% of these neurons are added within the first three postnatal months. Accordingly, cell proliferation and neurogenesis within the dentate gyrus peak within the first 3 months after birth and remain at an intermediate level between 3 months and at least 1 year of age. Although granule cell bodies undergo their largest increase in size during the first year of life, cell size and the volume of the three layers of the dentate gyrus (i.e. the molecular, granule cell and polymorphic layers) continue to increase beyond 1 year of age. Moreover, the different layers of the dentate gyrus exhibit distinct volumetric changes during postnatal development. Finally, we observe significant levels of cell proliferation, neurogenesis and cell death in the context of an overall stable number of granule cells in mature 5–10‐year‐old monkeys. These data identify an extended developmental period during which neurogenesis might be modulated to significantly impact the structure and function of the dentate gyrus in adulthood.     

Adulte Stammzellen in Patienten mit Temporallappenepilepsie

Adult stem cells persist in the subventricular zone and hippocampus (dentate gyrus) of the human brain. Surgical specimens obtained from patients with drug-resistant temporal lobe epilepsy (TLE) represent an important tool to study mechanisms of adult stem cells. The following issues are currently intensively discussed: (1) establishment of standardized in vitro protocols for the recruitment, proliferation, and differentiation of adult stem cells from human tissue obtained during surgery from TLE patients. (2) Can adult stem cells be used in the future for the targeted therapy of pharmacy-resistant focal epilepsy? (3) Which functions do adult stem cells or the newly formed nerve cells (neurogenesis) have in the human hippocampus? Since recent data from animal experiments support the notion that hippocampal neurogenesis is relevant in memory function, this knowledge may also offer intriguing insights into the memory deficits that commonly affect TLE patients.     

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.     

Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by reelin signaling mutant mice

During dentate gyrus development, the early embryonic radial glial scaffold is replaced by a secondary glial scaffold around birth. In contrast to neocortical and early dentate gyrus radial glial cells, these postnatal glial cells are severely altered with regard to position and morphology in reeler mice lacking the secreted protein Reelin. In this study, we focus on the functional impact of these defects. Most radial glial cells throughout the nervous system serve as scaffolds for migrating neurons and precursor cells for both neurogenesis and gliogenesis. Precursor cell function has been demonstrated for secondary radial glial cells but the exact function of these late glial cells in granule cell migration and positioning is not clear. No data exist concerning the interplay between granule neurons and late radial glial cells during dentate gyrus development. Herein, we show that despite the severe morphological defects in the reeler dentate gyrus, the precursor function of secondary radial glial cells is not impaired during development in reeler mice. In addition, selective ablation of Disabled‐1, an intracellular adaptor protein essential for Reelin signaling, in neurons but not in glial cells allowed us to distinguish effects of Reelin signaling on radial glial cells from possible secondary effects based on defective granule cells positioning. GLIA 2013;61:1347–1363     

The role of N-methyl-D-asparate receptors in neurogenesis

The dentate gyrus continues to incorporate granule neurons during adulthood. Among the factors that we know modulate adult neurogenesis in the dentate gyrus, one of the first studied was the influence of excitatory amino-acids. These neurotransmitters, acting through NMDA receptors, are able to modulate both the proliferation of progenitor cells as well as the rate of neurogenesis in the adult dentate gyrus. However, the mechanisms by which these processes are influenced are not clearly known. Although there is no anatomical evidence of NMDA receptor expression in adult hippocampal progenitor cells or differentiating granule neurons, electrophysiological data and in vitro studies suggest that NMDA receptors may be expressed by certain precursor cells and immature granule neurons. This review summarizes findings on the influence of pharmacological manipulation of NMDA receptors on adult neurogenesis. We also analyze previous studies that have suggested the expression of NMDA receptors in progenitors and immature granule cells and discuss the putative role of these receptors in the regulation of developmental processes such as proliferation, migration, or neurite outgrowth.     

Morphogenesis of the dentate gyrus: what we are learning from mouse mutants

The dentate gyrus is one of two locations with continuing neurogenesis in adult mammals. While the function of adult neurogenesis is unknown, it is believed that it is involved in learning and memory. For adult neurogenesis to occur, the dentate gyrus must maintain the appropriate precursor cell niche in the subgranular zone, which is likely to be dependent on the developmental mechanisms at play in forming the dentate gyrus. In this review, we graft a molecular framework onto the known neuroanatomic developmental plan by considering the phenotypes of several mouse mutants that have well characterized dentate gyrus developmental abnormalities. This effort reveals that there are at least six distinct developmental steps that need to occur in the formation of the dentate gyrus, which can be associated with specific gene defects: (1) defining the dentate neuroepithelium; (2) forming the primary radial glial scaffolding; (3) radial migration of granule neurons to form the primordial granule cell layer; (4) establishing the precursor pool in the hilus; (5) radial transformation of the tertiary matrix, and (6) differentiation of dentate granule cells. From this analysis, it is clear that some molecular pathways control multiple steps in the development of the dentate gyrus. For example the Wnt pathway (steps 1, 2, 4) and the chemokine receptor CXCR4 (steps 3, 4) are involved in multiple developmental steps, while the neuronal differentiation gene NeuroD (step 6) and the integrin signaling pathway (step 5) are involved only in discrete stages of the dentate gyrus morphogenesis.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.