Number Of Granule Cells Research Articles

The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration

During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and autism spectrum disorders.

Contribution of the neural cell recognition molecule NB‐3 to synapse formation between parallel fibers and Purkinje cells in mouse

The neural cell recognition molecule NB-3, also referred to as contactin-6, is expressed prominently in the developing nervous system after birth and its deficiency has been shown to cause impairment in motor coordination. Here, we investigated the contribution of NB-3 to cerebellar development, focusing on lobule 3 where NB-3 was expressed in granule cells but not in Purkinje cells. In the developing molecular layer, the neural cell recognition molecules TAG-1, L1, and NB-3 formed distinct expression zones from the external granule cell layer to the internal granule cell layer (IGL), respectively. The NB-3-immunoreactive zone did not overlap with TAG-1-immunoreactive zone. By contrast, the L1-immunoreactive zone overlapped with both the TAG-1- and NB-3-immunoreactive zones. NB-3-positive puncta overlapped with vesicular glutamate transporter 1, a presynaptic marker and were apposed close to metabotropic glutamate receptor 1A, a postsynaptic marker, indicating that NB-3 is localized presynaptically at glutamatergic synapses between parallel fibers and Purkinje cells. In NB-3 knockout mice, L1 immunoreactive signals were increased in the IGL at postnatal day (P) 5, suggesting the increase in the number of immature granule cells of the IGL. In addition, the density of parallel fiber synaptic terminals was reduced in NB-3 knockout mice relative to wild-type mice at P5 to P10. In parallel with these findings, caspase-dependent cell death was significantly increased in the NB- 3-deficient cerebellum at P15. Collectively, our results indicate that NB-3 deficiency affects synapse formation during postnatal cerebellar development.

The role of mast cells in non-ablative laser resurfacing with 1,320 nm neodymium:yttrium–aluminium–garnet laser

The aim of this study was to investigate the role of mast cells in mechanisms of collagen remodelling induced by non-ablative laser treatment. The dorsal skin of Kunming (KM) mice was exposed to 1,320 nm neodymium-yttrium-aluminium garnet (Nd:YAG) laser weekly for four consecutive weeks. Biopsies were taken 1 h after irradiation and 1 day, 7 days, 14 days, 30 days and 60 days after the first treatment. Skin samples were studied for mast cells, fibroblasts, and type I and III collagen, by toluidine blue, haematoxylin-eosin (HE) and immunohistochemical staining, respectively. The total number of mast cells in the skin of experimental group was significantly greater than that in the control at 1 h, 1 day, 21 days and 60 days after the first treatment (P < 0.05, respectively). At any of the time points studied, the number of degranulated mast cells in the experimental group was significantly higher than in the control (P < 0.01, P < 0.01, P < 0.05, P < 0.01, P < 0.05, P < 0.05, respectively).The number of fibroblasts in the experimental group exhibited a significant increase in comparison with those in control skin at days 7, 21, 30 and 60 after irradiation (P < 0.05, P < 0.01, P < 0.01, P < 0.05, respectively). The amount of type I collagen was significantly higher than in the control from day 21 to day 60 (P < 0.05, P < 0.01, P < 0.01, respectively), and type III collagen showed a marked increase between day 7 and day 60, compared with the control (P < 0.01, P < 0.05, P < 0.01, P < 0.01, respectively). There was a significant positive correlation between the number of fibroblasts and granulated mast cells (r = 0.549, P < 0.01). The amount of type I and III collagen also showed significant positive correlations with the number of degranulated mast cells (r = 0.555, P < 0.01 and r = 0.579, P < 0.01, respectively). The results suggested that dermal mast cells might be involved in the inflammatory response, fibroblast proliferation and collagen remodelling induced by non-ablative laser treatment.

RBP-J promotes neuronal differentiation and inhibits oligodendroglial development in adult neurogenesis

Neurogenesis persists in restricted regions of the adult vertebrate brain. However, the molecular mechanisms supporting adult neurogenesis are not fully understood. Here we demonstrated that C cell-specific deletion of RBP-J in the adult subventricular zones (SVZs) caused reduction in numbers of mature granule cells in the olfactory bulbs (OBs) with concomitant increase in Olig2 + oligodendroglial progenitors, although generation of immature neurons was enhanced in the SVZs. Adenovirus-mediated Cre introduction to the SVZs of RBP-J-floxed mice indicated that Olig2 + cells in the OBs can be generated from RBP-J-deficient SVZs, although no oligodendroglial cells in the OBs are derived from the normal SVZs. This preferential differentiation to oligodendroglial progenitor cells and reduction in differentiation of mature neurons were also confirmed by in vitro culture of RBP-J-deficient SVZ-derived neural progenitor cells, in addition to defects in the maintenance of adult neural stem cell population. The defects in maturation of RBP-J-deficient neurons could be partly rescued by knockdown of Olig2 in vivo. Our findings suggest that RBP-J might regulate neuronal maturation at least in part through transcriptional repression of Olig2.

Decreased levels of disrupted-in-schizophrenia 1 (DISC1) are associated with expansion of the dentate granule cell layer in normal and kindled rats

Disrupted-in-schizophrenia 1 (DISC1) is a candidate gene involved in the pathogenesis of schizophrenia. DISC1 expression is particularly abundant in the adult dentate gyrus, in which decreased levels lead to aberrant growth, impaired migration, and accelerated integration of adult generated neurons. Because seizures can also result in similar changes, we tested the hypothesis that DISC1 expression may be altered in an animal model of epilepsy. We found that extended amygdala kindling (i.e., 99-electrical stimulations) significantly decreased DISC1 labeling in the dentate granule cell layer and subgranular zone. Extended kindling also led to an increase in the number of ectopic granule cells in the hilus. In addition, although the width of the granule cell layer was not generally affected by kindling, decreased levels of DISC1 in the subgranular zone and granule cell layer were associated with an expansion of the upper blade and crest of the dentate gyrus in both normal and kindled rats. These novel findings suggest that seizure activity affects DISC1 signaling in the dentate gyrus and that DISC1 expression may regulate the cytoarchitectural organization of the granule cell layer.

Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease

An active lifestyle is to some degree protective against Alzheimer's disease (AD), but the biological basis for this benefit is still far from clear. We hypothesize that physical and cognitive activity increase a reserve for plasticity by increasing adult neurogenesis in the hippocampal dentate gyrus (DG). We thus assessed how age affects the response to activity in the murine APP23 model of AD compared with wild type (WT) controls and studied the effects of physical exercise (RUN) and environmental enrichment (ENR) in comparison with standard housing (CTR) at two different ages (6 months and 18 months) and in both genotypes. At 18 months, both activity paradigms reduced the hippocampal human Abeta1-42/Abeta1-40 ratio when compared with CTR, despite a stable plaque load in the hippocampus. At this age, both RUN and ENR increased the number of newborn granule cells in the DG of APP23 mice when compared with CTR, whereas the levels of regulation were equivalent to those in WT mice under the same housing conditions. At 6 months, however, neurogenesis in ENR but not RUN mice responded like the WT. Quantifying the number of cells at the doublecortin-positive stage in relation to the number of cells on postmitotic stages we found that ENR overproportionally increased the number of the DCX-positive "late" progenitor cells, indicative of an increased potential to recruit even more new neurons. In summary, the biological substrates for activity-dependent regulation of adult hippocampal neurogenesis were preserved in the APP23 mice. We thus propose that in this model, ENR even more than RUN might contribute to a "neurogenic reserve" despite a stable plaque load and that age affects the outcome of an interaction based on "activity."

Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain

Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.

Effects of prenatal exposure to a 900 MHz electromagnetic field on the dentate gyrus of rats: a stereological and histopathological study

Electromagnetic fields (EMFs) inhibit the formation and differentiation of neural stem cells during embryonic development. In this study, the effects of prenatal exposure to EMF on the number of granule cells in the dentate gyrus of 4-week-old rats were investigated. This experiment used a control (Cont) group and an EMF exposed (EMF) group (three pregnant rats each group). The EMF group consisted of six offspring ( n = 6) of pregnant rats that were exposed to an EMF of up to 900 megahertz (MHz) for 60 min/day between the first and last days of gestation. The control group consisted of five offspring ( n = 5) of pregnant rats that were not treated at all. The offspring were sacrificed when they were 4 weeks old. The numbers of granule cells in the dentate gyrus were analyzed using the optical fractionator technique. The results showed that prenatal EMF exposure caused a decrease in the number of granule cells in the dentate gyrus of the rats ( P < 0.01). This suggests that prenatal exposure to a 900 MHz EMF affects the development of the dentate gyrus granule cells in the rat hippocampus. Cell loss might be caused by an inhibition of granule cell neurogenesis in the dentate gyrus.

Axonal abnormalities in cerebellar Purkinje cells of the Ts65Dn mouse

Ts65Dn mice are a genetic model for Down syndrome. Among others, these mice have cerebellar pathology features which parallel those seen in Down syndrome patients. Both individuals with Down syndrome and Ts65Dn mice have reduced cerebellar volume and numbers of granule and Purkinje cells. In this report, we describe morphological abnormalities of axons of Purkinje cells in the cerebellum of Ts65Dn mice, by using anti-calbindin immunocytochemistry. A consistent number of Purkinje cells shows axons bearing giant varicosities along their transit through the granular layer. The cerebellar arbor vitae made by fasciculated Purkinje cell axons has a patchy appearance, some tracks being devoid of calbindin staining. The infraganglionic plexus, formed by recurrent collaterals of Purkinje cell axons, has enormously increased density, which is evidence for a compensatory reaction to degeneration of distal segments of axons. These alterations are accompanied by strong glial reaction as evidenced by GFAP immunocytochemistry. Moreover, the alterations are more consistent in the anterior lobules of the vermis and intermediate cortex. The axonal pathology of Purkinje cells may explain the impairment in cerebellar functions observed in Ts65Dn mice at the adulthood.

P.2.a.001 Efficacy of agomelatine from treatment initiation to treatment completion

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.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.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.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.

The Comparative Pathology of the Glycosidase Inhibitors Swainsonine, Castanospermine, and Calystegines A3, B2, and C1 in Mice

To study various polyhydroxy-alkaloid glycosidase inhibitors, 16 groups of 3 mice were dosed using osmotic minipumps with swainsonine (0, 0.1, 1, and 10 mg/kg/day), castanospermine, and calystegines A(3), B(2), and C(1) (1, 10, and 100 mg/kg/day). After 28 days, the mice were euthanized, necropsied, and examined using light and electron microscopy. The high-dose swainsonine-treated mice developed neurologic disease with neuro-visceral vacuolation typical of locoweed poisoning. Castanospermine- and calystegines-treated mice were clinically normal; however, high-dose castanospermine-treated mice had thyroid, renal, hepatic, and skeletal myocyte vacuolation. Histochemically, swainsonine- and castanospermine-induced vacuoles contained mannose-rich oligosaccharides. High-dose calystegine A(3)-treated mice had increased numbers of granulated cells in the hepatic sinusoids. Electron microscopy, lectin histochemistry, and immunohistochemistry suggest these are pit cells (specialized NK cells). Histochemically, the granules contain glycoproteins or oligosaccharides with abundant terminal N-acetylglucosamine residues. Other calystegine-treated mice were histologically normal. These findings indicate that swainsonine produced lesions similar to locoweed, castanospermine caused vacuolar changes with minor changes in glycogen metabolism, and only calystegine A(3) produced minimal hepatic changes. These also suggest that in mice calystegines and castanospermine are less toxic than swainsonine, and as rodents are relatively resistant to disease, they are poor models to study such induced storage diseases.

Mechanisms and functional significance of aberrant seizure‐induced hippocampal neurogenesis

Studies of experimental mesial temporal lobe epilepsy (mTLE) indicate that prolonged seizures in the adult not only damage the hippocampal formation but also dramatically stimulate neurogenesis. Endogenous neural progenitor cells (NPCs) located in the adult rodent dentate gyrus and striatal subventricular zone are stimulated by experimental status epilepticus (SE) to generate increased numbers of dentate granule cells (DGCs) and olfactory interneurons, respectively (Bengzon et al., 1997; Parent et al., 1997, 2002; Scott et al., 1998). In this review, we discuss current knowledge regarding the consequences of seizure activity on NPC proliferation, focusing on the hippocampus, and on the migration and integration of adult-born hippocampal neurons. We also describe the effects of seizure-induced neurogenesis on hippocampal network function and the potential relevance of aberrant neurogenesis to human mTLE.

Early age-related changes in adult hippocampal neurogenesis in C57 mice

Strong age-related declines in conjunction with comparatively easy experimental manipulations of adult hippocampal neurogenesis have generated considerable public and scientific interest in the prospect of “new neurons for old brains”. Only few studies addressed the time course of the natural changes, which are the substrate for interventions that may realize this prospect. We provide a monthly or bimonthly account of cell proliferation, neurogenesis and cell death during the first 9 months of the life of C57Bl/6J mice. Ki67- and DCX-positive cell numbers declined exponentially without an intermittent plateau (∼40% per month). Cell death in relation to cell proliferation was lowest at 1 month, increased at 2 months to remain constant until 4 months, and decreased again at 5 months to remain stable until 9 months. Granule cell number did not change with age. Our results suggest that manipulations of proliferation and neurogenesis may, at any time, interact with strong natural changes of these processes. Mediators of their age-related decline may be studied over periods much shorter than those typically used.

Automatic sampling for unbiased and efficient stereological estimation using the proportionator in biological studies

Quantification of tissue properties is improved using the general proportionator sampling and estimation procedure: automatic image analysis and non-uniform sampling with probability proportional to size (PPS). The complete region of interest is partitioned into fields of view, and every field of view is given a weight (the size) proportional to the total amount of requested image analysis features in it. The fields of view sampled with known probabilities proportional to individual weight are the only ones seen by the observer who provides the correct count. Even though the image analysis and feature detection is clearly biased, the estimator is strictly unbiased. The proportionator is compared to the commonly applied sampling technique (systematic uniform random sampling in 2D space or so-called meander sampling) using three biological examples: estimating total number of granule cells in rat cerebellum, total number of orexin positive neurons in transgenic mice brain, and estimating the absolute area and the areal fraction of beta islet cells in dog pancreas. The proportionator was at least eight times more efficient (precision and time combined) than traditional computer controlled sampling.

Early-life status epilepticus induces ectopic granule cells in adult mice dentate gyrus

A large number of aberrant hilar granule cells (GCs) are found in the patients and animal models of adult temporal lobe epilepsy (TLE), and these “ectopic” GCs have synchronous epileptiform bursting with other hippocampal neurons. In this study, we investigated whether early-life status epilepticus (SE) induces hilar ectopic GCs that remain in the adulthood because TLE patients frequently experience seizures in the early childhood when a large number of postnatally born GCs migrate in the hilus. To label newborn GCs, bromodeoxyuridine (BrdU) was injected daily for three consecutive days to C57BL/6J mice at different postnatal days starting at postnatal-0-day-old (P0) (Group1), P7 (Group2), or P35 (Group3). Mice in each group underwent pilocarpine-induced SE at P14. Six months later, to determine whether SE induces ectopic GCs, we plotted the distribution of postnatally born GCs which were immunohistochemically defined as BrdU- and the GC marker Prox1-colabeled cells. We also examined whether SE causes the granule cell layer (GCL) dispersion and/or the mossy fiber (MF) sprouting, other representative pathologies of TLE hippocampus. Only SE-experiencing mice in Group1 had significantly more neonatally born ectopic GCs compared with control mice. Neither control nor SE mice had dispersed GCL. All mice that underwent SE had sprouted MFs in CA3. We conclude that early-life SE disrupts a normal incorporation of GCs born pre-SE but not post-SE, inducing ectopic GCs in the adult hilus. Interestingly, the results also indicate that developmentally earlier born GCs are more responsive to early-life SE in terms of the emergence of ectopic GCs.

Red Wine, but not Port Wine, Protects Rat Hippocampal Dentate Gyrus Against Ethanol-Induced Neuronal Damage--Relevance of the Sugar Content

Chronic ethanol consumption leads to oxidative damage in the central nervous system inducing neuronal degeneration and impairment of brain functions. Nevertheless, it has been reported that grape polyphenols might prevent the alluded ethanol effects. We have reported that prolonged red wine intake improves hippocampal formation oxidative status, a finding not replicated using Port wine. Thus, we thought of interest to compare the effects of chronic ingestion of these wines in the morphology of dentate gyrus (DG) neurons that are particularly vulnerable to alcohol effects. Six-month-old Wistar rats were fed either with red wine or Port wine (both with 20% ethanol content, v/v), and the results were compared with 20% (v/v) ethanol-treated, ethanol/glucose and pair-fed control groups. After 6 months of treatment, the layer volumes of the DG and the total number of granule and hilar neurons were estimated. The dendritic trees of granule cells were also studied in Golgi-impregnated material. The number of granule cells and the DG layer volumes were similar among all groups. However, the number of hilar neurons was reduced in Port wine, ethanol-treated and ethanol/glucose animals. Furthermore, the granule cells from these groups showed a decrease in the total dendritic length. Although the Port wine and red wine have similar amounts of flavanols with identical ability to protect against oxidative stress, the differences observed are probably related to the very dissimilar processes of wine production, leading in Port wine to a high content of sugars, which are known to have potent pro-oxidant effects.

GluR2 expressed by glial fibrillary acidic protein promoter decreases the number of neurons

The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) type ionotropic glutamate receptors participate in fast neuronal transmission. GluR2, a subunit of AMPA receptors, is the determinant of Ca2+-permeability and surface expression of the receptors. To elucidate the role of AMPA receptors in the cells expressing glial fibrillary acidic protein (GFAP), we constructed mice expressing rat GluR2 cDNA under the control of a human GFAP promoter. The mice expressed approximately two folds increase of GluR2 in primary culture of astrocytes. Colocalization of GluR2 and GFAP was observed in Bergmann glial cells, which normally expressed AMPA receptors lacking GluR2. The diameter of glial fibers was significantly reduced and the leading edge of the processes was thinning or retracted in primary cultured BG cells. Interestingly, the transgenic mice had smaller brains compared with wild type mice. We found a 32% decrease in the number of cerebellar granule cells and a 31% decreases in cerebral cortical neurons. These results indicate that the increased expression of GluR2 in GFAP-positive cells alters neuron-glial interaction and leads to reduction in the number of neurons in adult mice.

The number of granule cells in rat hippocampus is reduced after chronic mild stress and re-established after chronic escitalopram treatment

Stress and depression cause structural changes in the hippocampal formation. Some of these can be reversed by chronic antidepressant treatment. In the present study, we examined the changes in the total number of granule cells and the volume of the granule cell layer after exposing rats to chronic mild stress and chronic escitalopram treatment. Furthermore, we investigated which classes of immature granule cells are affected by stress and targeted by escitalopram. Rats were initially exposed to 2 weeks of CMS and 4 weeks of escitalopram treatment with concurrent exposure to stress. The behavioral changes, indicating a decrease in sensitivity to a reward, were assessed in terms of sucrose consumption. We found a significant 22.4% decrease in the total number of granule cells in the stressed rats. This decrease was reversed in the stressed escitalopram treated rats that responded to the treatment, but not in the rats that did not respond to escitalopram treatment. These changes were not followed by alterations in the volume of the granule cell layer. We also showed a differential regulation of dentate neurons, in different stages of development, by chronic stress and chronic escitalopram treatment. Our study shows that the anhedonia-like state in the CMS rats is associated with a reduced number of granule cells. We conclude that escitalopram acts on specific cellular targets during neuronal differentiation and that recovery from anhedonia-like behavior in rats may be the consequence of an escitalopram mediated increase in specific subtypes of immature dentate neurons.

P1-42 Placental restriction leads to an upregulation of the angiotensin II receptors AT1R and AT2R mRNA in the aorta of the fetal sheep in late gestation

Studies in rats and mice have shown several sex-dependent functional and structural differences in the hippocampal region, a brain structure playing a key role in learning and memory. The aim of the present study was to establish whether sex differences exist prior to puberty in the stereological parameters of the dentate gyrus in the guinea-pig, a long-gestation rodent, whose brain is at a more advanced stage of maturation at birth than the rat and mouse. The number of granule cells and volumes of the granule cell layer, molecular layer and hilus were evaluated in Nissl-stained brains of neonatal (15–16 days old) and peripubescent (45–46 days old) guinea-pigs. Based on a pilot study, the optical disector method was preferred to the optical fractionator method to estimate cell number. For volume (Vref) estimation with the Cavalieri principle, contour tracing was preferred to the point counting method, as the latter appeared to underestimate volumes. The results showed that neonatal males had more granule cells than females in both the dorsal and ventral dentate gyrus and a larger volume in all layers. Peripubescent males had a larger volume of the granule cell layer than females in both the dorsal and ventral dentate gyrus, more granule cells in the ventral dentate gyrus, a larger volume of the hilus in both the dorsal and ventral dentate gyrus and a larger volume of the molecular layer in the ventral dentate gyrus. The results show that sex differences are present in the guinea-pig dentate gyrus prior to puberty and go in the same direction at both investigated ages, with males exhibiting more granule cells and larger volumes than females. The widespread distribution of these sex differences suggests that in the guinea-pig, similarly to other rodents, hippocampus-dependent functions may be sexually dimorphic.

Seizure-Associated, Aberrant Neurogenesis in Adult Rats Characterized with Retrovirus-Mediated Cell Labeling

Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.