Systemic Injection of Kainic Acid Differently Affects LTP Magnitude Depending on its Epileptogenic Efficiency

Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72–85% rats). A group of rats were resistant to develop SE (15–28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals’ performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency.     

Morphological changes in the hippocampus following nicotine and kainic acid administration

Using histochemical analysis (NADPH-diaphorase, Fluoro-Jade B dye and bis-benzimide 33,342 Hoechst) we studied the influence of intraperitoneal administration of nicotine (NIC), kainic acid (KA) and combination of both these substances on hippocampal neurons and their changes. In experiments, 35-day-old male rats of the Wistar strain were used. Animals were pretreated with 1 mg/kg of nicotine 30 min prior to the kainic acid application (10 mg/kg). After two days, the animals were transcardially perfused with 4 % paraformaldehyde under deep thiopental anesthesia. Cryostat sections were stained to identify NADPH-diaphorase positive neurons that were then quantified in the CA1 and CA3 areas of the hippocampus, in the dorsal and ventral blades of the dentate gyrus and in the hilus of the dentate gyrus. Fluoro-Jade B positive cells were examined in the same areas in order to elucidate a possible neurodegeneration. In animals exposed only to nicotine the number of NADPH-diaphorase positive neurons in the CA3 area of the hippocampus and in the hilus of the dentate gyrus was higher than in controls. In contrast, KA administration lowered the number of NADPH-diaphorase positive cells in all studied hippocampal areas and in both blades of the dentate gyrus. Massive cell degeneration was observed in CA1 and CA3 areas of the hippocampus and in the hilus of the dentate gyrus after kainic acid administration. Animals exposed to kainic acid and pretreated with nicotine exhibited degeneration to a lesser extent and the number of NADPH-diaphorase positive cells was higher compared to rats, which were exposed to kainic acid only.     

Evaluation of the neuroprotective activity of stansin 6, a resin glycoside from Ipomoea stans

Stansin 6 a tetrasaccharide resin glycoside isolated from the root of Ipomoea stans was evaluated as anticonvulsant and neuroprotective in kainic acid-induced seizures of rats. Intraperitoneal injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures, and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Stansin 6 (10–80 mg/kg) had no effect on the behavior of rats and did not induce hippocampal damage. Pretreatment with stansin 6 inhibited convulsions in rats from kainic acid-induced seizures, reduced the degeneration pattern in the CA3 region, decreased astrocytic reactivity, and reduced the expression of IL-1β and TNF-α induced by kainic acid. These results suggest that stansin 6 possesses neuroprotective and anticonvulsant activities.     

Short-term alterations in hippocampal glutamate transport system caused by one-single neonatal seizure episode: implications on behavioral performance in adulthood

Impairment in the activity and expression of glutamate transporters has been found in experimental models of epilepsy in adult animals. However, there are few studies investigating alterations on glutamate transporters caused by epilepsy in newborn animals, especially in the early periods after seizures. In this study, alterations in the hippocampal glutamate transporters activity and immunocontent were investigated in neonatal rats (7 days old) submitted to kainate-induced seizures model. Glutamate uptake, glutamate transporters (GLT-1, GLAST, EAAC1) and glutamine synthetase (GS) were assessed in hippocampal slices obtained 12 h, 24 h, 48 h, 72 h and 60 days after seizures. Immunoreactivity for hippocampal GFAP, NeuN and DAPI were assessed 24 h after seizure. Behavioral analysis (elevated-plus maze and inhibitory avoidance task) was also investigated in the adult animals (60 days old). The decrease on glutamate uptake was observed in hippocampal slices obtained 24 h after seizures. The immunocontent of GLT-1 increased at 12 h and decreased at 24 h (+62% and −20%, respectively), while GLAST increased up to 48 h after seizures. No alterations were observed for EAAC1 and GS. It should be mentioned that there were no long-term changes in tested glutamate transporters at 60 days after kainate treatment. GFAP immunoreactivity increased in all hippocampal subfields (CA1, CA3 and dentate gyrus) with no alterations in NeuN and DAPI staining. In the adulthood, kainate-treated rats showed anxiety-related behavior and lower performance in the inhibitory avoidance task. Our findings indicate that acute modifications on hippocampal glutamate transporters triggered by a single convulsive event in early life may play a role in the behavioral alterations observed in adulthood.     

Progesterone,administered before kainic acid,prevents decrements in cognitive performance in the Morris Water Maze

The nature of progesterone (P₄)'s neuroprotective effects is of interest. We investigated effects of P₄ when administered before, or after, kainic acid, which produces ictal activity and damage to the hippocampus, to mediate effects on spatial performance. The hypothesis was that P₄, compared with vehicle, would reduce decrements in Morris Water Maze performance induced by kainic acid. Experiment 1: We examined the effects of kainic acid on plasma stress hormone, corticosterone, and progestogen (P₄ and its metabolites) levels in plasma and the hippocampus after subcutaneous (s.c.) P₄ administration to ovariectomized rats. Rats administered kainic acid had the highest corticosterone levels immediately following injection. P₄ is 5α‐reduced to dihydroprogesterone (DHP) and subsequently metabolized to 5α‐pregnan‐3α‐ol‐20‐one (3α,5α‐THP) by 3α‐hydroxysteroid dehydrogenase. The regimen of P₄ used produced circulating and hippocampal levels of P₄, DHP, and 3α,5α‐THP within a physiological range, which declined at 14 hours postinjection and were not altered by kainic acid. Experiment 2: The physiological P₄ regimen was administered to rats before, or after, kainic acid‐induced seizures, and later effects on water maze performance were compared with that of rats administered vehicle. Rats administered kainic acid had significantly poorer performance in the water maze (i.e., increased latencies and distances to the hidden platform) than did rats administered vehicle. Administration of P₄ before, but not after, kainic acid prevented these performance deficits. Thus, these data suggest that a physiological regimen of P₄ can prevent some of the deficits in water maze performance produced by kainic acid. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 71: 142‐152, 2011     

Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model

Status epilepticus (SE) is a condition of persistent seizure that leads to brain damage and, frequently, to the establishment of chronic epilepsy. Cord blood is an important source of adult stem cells for the treatment of neurological disorders. The present study aimed to evaluate the effects of human umbilical cord blood mononuclear cells (HUCBC) transplanted into rats after induction of SE by the administration of lithium and pilocarpine chloride. Transplantation of HUCBC into epileptic rats protected against neuronal loss in the hippocampal subfields CA1, CA3 and in the hilus of the dentate gyrus, up to 300 days after SE induction. Moreover, transplanted rats had reduced frequency and duration of spontaneous recurrent seizures (SRS) 15, 120 and 300 days after the SE. Our study shows that HUCBC provide prominent antiepileptic and neuroprotective effects in the experimental model of epilepsy and reinforces that early interventions can protect the brain against the establishment of epilepsy.     

Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy

Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT₁ receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT₁ receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT₁ receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT₁ receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT₁ receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.     

Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility

Prolonged seizures in early childhood are associated with an increased risk of development of epilepsy in later life. The mechanism(s) behind this susceptibility to later development of epilepsy is unclear. Increased synaptic activity during development has been shown to permanently alter excitatory neurotransmission and could be one of the mechanisms involved in this increased susceptibility to the development of epilepsy. In the present study we determine the effect of status-epilepticus induced by lithium/pilocarpine at postnatal day 10 (P10 SE) on the expression of glutamate receptor and transporter mRNAs in hippocampal dentate granule cells and protein levels in dentate gyrus of these animals in adulthood. The results revealed a decrease in glutamate receptor 2 (GluR2) mRNA expression and protein levels as well as an increase in protein levels for the excitatory amino acid carrier 1 (EAAC1) in P10 SE rats compared to controls. Expression of glutamate receptor 1 (GluR1) mRNA was decreased in both P10 SE rats and identically handled, lithium-injected littermate controls compared to naive animals, and GluR1 protein levels were significantly lower in lithium-controls than in naive rats, suggesting an effect of either the handling or the lithium on GluR1 expression. These changes in EAA receptors and transporters were accompanied by an increased susceptibility to kainic acid induced seizures in P10 SE rats compared to controls. The current data suggest that early-life status-epilepticus can result in permanent alterations in glutamate receptor and transporter gene expression, which may contribute to a lower seizure threshold.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory

Impairment of cognitive functions including hippocampus-dependent spatial learning and memory affects nearly half of the aged population. Age-related cognitive decline is associated with synaptic dysfunction that occurs in the absence of neuronal cell loss, suggesting that impaired neuronal signaling and plasticity may underlie age-related deficits of cognitive function. Expression of myelin-associated inhibitors (MAIs) of synaptic plasticity, including the ligands myelin-associated glycoprotein, neurite outgrowth inhibitor A, and oligodendrocyte myelin glycoprotein, and their common receptor, Nogo-66 receptor, was examined in hippocampal synaptosomes and Cornu ammonis area (CA)1, CA3 and dentate gyrus subregions derived from adult (12-13 months) and aged (26-28 months) Fischer 344 × Brown Norway rats. Rats were behaviorally phenotyped by Morris water maze testing and classified as aged cognitively intact (n = 7-8) or aged cognitively impaired (n = 7-10) relative to adults (n = 5-7). MAI protein expression was induced in cognitively impaired, but not cognitively intact, aged rats and correlated with cognitive performance in individual rats. Immunohistochemical experiments demonstrated that up-regulation of MAIs occurs, in part, in hippocampal neuronal axons and somata. While a number of pathways and processes are altered with brain aging, we report a coordinated induction of myelin-associated inhibitors of functional and structural plasticity only in cognitively impaired aged rats. Induction of MAIs may decrease stimulus-induced synaptic strengthening and structural remodeling, ultimately impairing synaptic mechanisms of spatial learning and memory and resulting in cognitive decline.     

Spatiotemporal profile of N-cadherin expression in the mossy fiber sprouting and synaptic plasticity following seizures

Recurrent seizures can induce mossy fiber sprouting (MFS), of the hippocampal dentate gyrus, and synaptic reorganization in mature brain. This changes local circuits and provides a structural basis for epileptogenesis in the hippocampus. However, the mechanisms of MFS and synaptic reorganization still remain unclear. Neural-cadherin (N-cadherin), a calcium adhesion molecule, plays an important role in neurite outgrowth, pathfinding, and synaptic specificity of early central nervous system development. It is unknown whether N-cadherin is involved in MFS after seizures in mature brain. To further examine the correlation between MFS and N-cadherin expression, we separately labeled MFS and N-cadherin with Timm staining and antibody in adult rats after status epilepticus (SE). Timm staining revealed that MFS is observed in the inner molecular layer of dentate gyrus of rats 2 and 4 weeks after SE. The observed MFS migrated from the hilus to the granule cell layer, gradually extending axons into the inner molecular layer to form an intense band. Immunohistochemical staining of N-cadherin revealed that the upregulated expression of N-cadherin was concentrated in the position of mossy fiber axonal sprouts of rats 1-4 weeks after SE, and that it was earlier than MFS. The spatial and temporal distribution consistence of N-cadherin and Timm staining supported the correlation that exists between N-cadherin expression and the process of aberrant MFS. This result suggests that N-cadherin may be involved in the pathfinding and synaptic specificity of MFS in mature brain after seizures, and can play an important role in the targeted growth of mossy fibers.     

BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity.

Brain-derived neurotrophic factor (BDNF) mRNA expression was studied in the hippocampus at various developmental stages in normal rats and following kainic acid (KA)-induced seizure activity. Systemic administration of KA strongly elevated BDNF mRNA levels in all hippocampal subregions after postnatal day 21. In contrast, even though KA induced intense behavioral seizure activity at postnatal day 8, the seizures were not associated with elevations of BDNF mRNA levels, indicating a clear dissociation between behavioral seizures and increases in BDNF mRNA levels and contradicting the view that BDNF mRNA expression is principally regulated by neuronal activity. In the dentate gyrus at postnatal day 13, intense BDNF mRNA expression was limited to a defined area at the border between granule cell and molecular layers, suggesting the possibility that segregation of BDNF mRNA into defined subcellular compartments may play a role in establishing the well-delineated patterns of innervation in the hippocampus.     

Calcium in hippocampus following lidocaine induced seizures: an electron cytochemical study

The effect of lidocaine seizures on cellular accumulation of calcium was studied in hippocampal subfields CA1 and CA3 and the dentate gyrus of rats, using the combined oxalate-pyroantimonate method. The specificity of the reaction was ascertained by EGTA treatment and X-ray microanalysis. In control rats, calcium was visualized between myelin lamellae of axons, in synaptic vesicles and in some lysosomes. Two hours after onset of lidocaine seizures selective neuronal degenerations appeared in hippocampal subfields CA1 and CA3 but not in the dentate gyrus. Calcium deposits were present in numerous mitochondria of pyramidal cells and, occasionally, also of neuroglial cells. Many of these mitochondria exhibited ultrastructural alterations. Calcium uptake was most prominent in the CA3 sector but was also present in the CA1 subfield as well as the dentate gyrus. Intracellular calcium uptake, in consequence, is not the unique attribute of selectively vulnerable hippocampal neurons.     

CCL28 in the mouse hippocampal CA1 area and the dentate gyrus during and after pilocarpine-induced status epilepticus

The present study showed a wide presence of CCL28 in mouse CNS, including cerebral, cerebellum, brain stem and spinal cord. In hippocampus, the expression of CCL28 at both mRNA and protein level was clarified. The CCL28 expression was mainly localized in pyramidal cells of CA area, granular cells of dentate gyrus and some interneurons in CA area and hilus. Double-labelling immunocytochemistry revealed that most of calbindin, calretinin and parvalbumin immunopositive neurons expressed CCL28. During and after pilocarpine induced status epilepticus (SE), a down-regulated expression of CCL28 in hippocampal interneurons in the CA1 area and in the hilus of the dentate gyrus was demonstrated. The present study may, therefore provide evidence that CCL28 may have a novel role in CNS and may be involved in the loss of hippocampal interneurons, and subsequent disinhibition of pyramidal neurons.     

Effect of Seizures Induced by Intra-Amygdaloid Kainic Acid on Kainic Acid Binding Sites in Rat Hippocampus and Amygdala

[3H]Kainic acid binding sites with a slow dissociation rate in the rat limbic system were investigated in detail. Extensively washed membranes prepared from the hippocampal formation and from the region comprising the amygdala and the piriform cortex yielded non-linear Scatchard plots. Microdissection showed that the high-affinity component (affinity constant around 1 nM) was present in the hippocampal CA3 region (4.2 fmol/mg wet tissue) and the amygdaloid complex (4.6 fmol/mg wet tissue), whereas the remaining part of the hippocampal formation and the piriform lobe contained the low-affinity component (affinity constant 5-20 nM; 11.6 and 11.3 fmol/mg wet tissue, respectively). In the lateral + medial septum we detected only the low-affinity component. Severe limbic seizures, induced by unilateral injection of 0.7 or 0.8 microgram kainic acid in 0.3 microliter of phosphate-buffered saline into the amygdala, reduced kainic acid binding sites in the ipsilateral amygdala and CA3 region. The decline of kainic acid binding sites in the injected amygdala was followed by a similar effect in the contralateral amygdala ("mirror focus") and later by a moderate loss also in the contralateral CA3 region. Kainic acid receptor autoradiography demonstrated that binding sites were lost from the stratum lucidum in hippocampus. Septal lesion had no effect on kainic acid binding sites in the hippocampus. Comparison with previous results on the histopathological changes after this lesion shows that high-affinity kainic acid binding sites are preferentially located on neurons that undergo selective degenerations after severe kainic acid-induced seizures.     

海仁酸致痫大鼠海马组织AMPA受体GluR2表达的变化

目的　为了研究AMPA受体在癫痫发生中的作用。方法　本研究用免疫组织化学方法观察了海仁酸致痫大鼠海马组织AMPA GluR2受体的表达变化。结果　在侧脑室注射海仁酸后 1h ,4h ,12h ,2 4h及 7d ,大鼠海马CA3区及齿状回GluR2的表达明显减弱 ,显微图像分析 :与对照组相比 ,KA 4h ,KA 12h ,KA 2 4h ,KA 7d组大鼠海马组织GluR2阳性神经元平均光密度值降低 ,差异有显著性 (P <0 0 5 )。结论　在癫痫发作过程中AMPA受体 GluR2亚单位表达改变可能与癫痫发作导致的神经元损伤有密切关系。     

高脂饲养青春期大鼠电击回避反应和海马CA3区场电位的改变

目的：观察高脂饲养至青春期的大鼠对电击回避反应和海马CA3区实时局部场电位变化。方法：断乳1周幼鼠改用基础饲料和高脂饲料分别喂养4周至青春期,分为基础饲料组（BF组）和高脂饲料组（HFD组）,Y型迷宫电击回避训练方法,记录2组大鼠电击回避达学会标准的相关参数,同时无线遥测大鼠达标时海马CA3区实时局部场电位。结果：与BF组大鼠比较,HFD组大鼠体重明显增加,Y型迷宫电击回避训练1~2 d大鼠达标百分率、电击回避达标各项指标均略优于BF组;双侧海马CA3区局部场电位节律出现去同步化快波改变,右侧海马CA3区出现了θ波和γ 1波百分比的同步性增加,但无θ~γ 1波相位-振幅耦合出现。结论：幼年期短期高脂饮食至青春期的大鼠,尽管体重较基础饲料大鼠增加,但未见Y型迷宫电击回避反应能力和海马依赖性空间认知功能的减退。     

GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy, characterized by recurrent complex partial seizures and hippocampal sclerosis. The pathophysiology underlying this disorder remains unidentified. While a loss of benzodiazepine binding sites is a key diagnostic feature of MTLE, experimental studies have shown enhanced inhibitory transmission and increased expression of GABA(A)-receptors, suggesting that compensatory mechanisms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABA(A)-receptor subunits were investigated in the hippocampus of pilocarpine-treated rats during the phase of spontaneous recurrent seizures. A uniform decrease in GABA(A)-receptor subunit-immunoreactivity was observed in regions of extensive neuronal death (i.e. CA1, CA3, hilus). whereas a prominent increase occurred in the dentate gyrus (DG). Most strikingly, the increase was largest for the alpha3- and alpha5-subunits, which are expressed at very low levels in the DG of control rats, suggesting the formation of novel GABA(A)-receptor subtypes in epileptic tissue. Furthermore, an extensive loss of interneurons expressing the alpha1-subunit, representing presumptive basket cells, was seen in the DG. These changes were very similar to those reported in a novel mouse model of MTLE, based on the unilateral injection of kainic acid into the dorsal hippocampus (Bouilleret et al., 1999). This indicates that the regulation of GABA(A)-receptor expression is related to chronic recurrent seizures, and is not due to the extrahippocampal neuronal damage affecting pilocarpine-treated rats. These results allow causal relationships in the induction and maintenance of chronic recurrent seizures to be distinguished. The loss of a critical number of interneurons in the DG is a possible cause of seizure initiation, whereas the long-lasting upregulation of GABA(A)-receptors in granule cells represents a compensatory response to seizure activity.     

Role of limbic structures in the mechanisms of post-traumatic epilepsy]

It was shown in the experiments on rats that intracerebroventricular administration of kainic acid (0.01, 0.05 microgram) after brain trauma, resulted in the occurrence of behavioral and electrographic convulsive disturbances; maximal expression of epileptic activity was obtained in entorhinal cortex and ventral hippocampus. Kainic acid induced epileptic reactions in nontraumatized rats only if injected in dose 0.1 microgram. Brain trauma did not lead to changes in seizures intensity induced by systemic picrotoxin administration. It is concluded that the formation of generator of pathologically enhanced excitation in limbic structures via increase of excitor glutamatergic neurotransmission is the important mechanism of traumatic epilepsy.     

Neural stem cell apoptosis after low‐methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits

The developing brain is particularly sensitive to exposures to environmental contaminants. In contrast to the adult, the developing brain contains large numbers of dividing neuronal precursors, suggesting that they may be vulnerable targets. The postnatal day 7 (P7) rat hippocampus has populations of both mature neurons in the CA1–3 region as well as neural stem cells (NSC) in the dentate gyrus (DG) hilus, which actively produce new neurons that migrate to the granule cell layer (GCL). Using this well‐characterized NSC population, we examined the impact of low levels of methylmercury (MeHg) on proliferation, neurogenesis, and subsequent adolescent learning and memory behavior. Assessing a range of exposures, we found that a single subcutaneous injection of 0.6 µg/g MeHg in P7 rats induced caspase activation in proliferating NSC of the hilus and GCL. This acute NSC death had lasting impact on the DG at P21, reducing cell numbers in the hilus by 22% and the GCL by 27%, as well as reductions in neural precursor proliferation by 25%. In contrast, non‐proliferative CA1–3 pyramidal neuron cell number was unchanged. Furthermore, animals exposed to P7 MeHg exhibited an adolescent spatial memory deficit as assessed by Morris water maze. These results suggest that environmentally relevant levels of MeHg exposure may decrease NSC populations and, despite ongoing neurogenesis, the brain may not restore the hippocampal cell deficits, which may contribute to hippocampal‐dependent memory deficits during adolescence. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 936–949, 2013