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PubMed1994

The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis.

The factors contributing to selective motoneuron loss in amyotrophic lateral sclerosis (ALS) remain undefined. To investigate whether calcium-binding proteins contribute to selective motoneuron vulnerability in ALS, we compared calbindin-D28K and parvalbumin immunoreactivity in motoneuron populations in human ALS, and in a ventral spinal cord hybrid cell line selectively vulnerable to the cytotoxic effects of ALS IgG. In human autopsy specimens, immunoreactive calbindin-D28k and parvalbumin were absent in motoneuron populations lost early in ALS (i.e., cortical and spinal motoneurons, lower cranial nerve motoneurons), while motoneurons damaged late or infrequently in the disease (i.e., Onuf's nucleus motoneurons, oculomotor, trochlear, and abducens nerve neurons) expressed markedly higher levels of immunoreactive calbindin-D28K and/or parvalbumin. Motoneuron-neuroblastoma VSC 4.1 hybrid cells lost immunoreactive calbindin-D28k and parvalbumin following dibutyryl-cyclic AMP-induced differentiation and were killed by IgG from ALS patients. Undifferentiated calbindin/parvalbumin-reactive VSC 4.1 cells were not killed, nor were other cell lines expressing high levels of calbindin-D28K and parvalbumin immunoreactivity (substantia nigra-neuroblastoma hybrid cells and N18TG2 neuroblastoma parent cells). These studies suggest that decreased calbindin-D28K and parvalbumin immunoreactivity may help explain the selective vulnerability of motoneurons in ALS.

Adult↗

PubMed2000

AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability.

AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have been shown in various models to be more susceptible to AMPA receptor-mediated injury than other spinal neurons. It has been hypothesized that this selective vulnerability of motoneurons is caused by the expression of highly Ca(2+)-permeable AMPA receptors and a complete or relative lack of the AMPA receptor subunit Glu receptor 2 (GluR2). The aim of this study was to quantify the relative Ca(2+) permeability of AMPA receptors and the fractional expression of GluR2 in motoneurons by combining whole-cell patch-clamp electrophysiology and single-cell RT-PCR and to compare these properties with those of dorsal horn neurons. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. As in previous studies, motoneurons were significantly more vulnerable to AMPA and kainate than dorsal horn neurons. However, all motoneurons expressed GluR2 mRNA ( approximately 40% of total AMPA receptor subunit mRNA), and their AMPA receptors had intermediate whole-cell relative Ca(2+) permeability (P(Ca(2+))/P(Cs(+)) approximately 0. 4). AMPA receptor P(Ca(2+))/P(Cs(+)) and the relative abundance of GluR2 varied more widely in dorsal horn neurons than in motoneurons, but the mean values did not differ significantly between the two cell populations. GluR2 was virtually completely edited at the Q/R site both in motoneurons and dorsal horn neurons. These results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca(2+) permeability of AMPA receptors.

Amyotrophic Lateral Sclerosis↗

PubMed1998

Selective glial vulnerability following transient global ischemia in rat brain.

Global cerebral ischemia selectively damages neurons, but its contribution to glial cell death is uncertain. Accordingly, adult male rats were sacrificed by perfusion fixation at 1, 2, 3, 5, and 14 days following 10 minutes of global ischemia. This insult produces CA1 hippocampal neuronal death at post-ischemic (PI) day 3, but minor or no damage to neurons in other regions. In situ end labeling (ISEL) and immunohistochemistry identified fragmented DNA of dead or dying glia and distinguished glial subtypes. Rare ISEL-positive oligodendroglia, astrocytes, and microglia were present in control brain. Apoptotic bodies and ISEL-positive glia significantly increased at PI day 1 in cortex and thalamus (p < 0.05), but were similar to controls in other regions and at other PI intervals. Most were oligodendroglia, although ISEL-positive microglia and astrocytes were also observed. These results show that oligodendroglia die rapidly after brief global ischemia and are more sensitive than neurons in certain brain regions. Their selective vulnerability to ischemia may be responsible for the delayed white matter damage following anoxia or CO poisoning or that associated with white matter arteriopathies. Glial apoptosis could contribute to the DNA ladders of apoptotic oligonucleosomes that have been found in post-ischemic brain.

Animals↗

PubMed2003

Selective neuronal vulnerability following mild focal brain ischemia in the mouse.

The evolution of cellular damage over time and the selective vulnerability of different neuronal subtypes was characterized in the striatum following 30-minute middle cerebral artery occlusion and reperfusion in the mouse. Using autoradiography we found an increase in the density of [3H]PK11195 binding sites--likely reflecting microglial activation--in the lesion border at 3 days and in the whole striatum from 10 days to 6 weeks. This was accompanied by a distinct loss of [3H]flumazenil and [3H]CGP39653 binding sites from 10 days up to 6 weeks reflecting neuronal loss. Brain ischemia resulted in a substantial loss of medium spiny projection neurons as seen at three days by Nissl staining, TUNEL and immunocytochemistry using antibodies against microtubule-associated protein (MAP2), NeuN, mu-opioid receptors, substance P, L-enkephalin, neurokinin B, choline acetyltransferase, parvalbumin, calretinin and somatostatin. Both patch and matrix compartments were involved in ischemic damage. In contrast, the numbers of cholinergic, GABAergic, and somatostatin-containing interneurons in the ischemic striatum were not different from those in the contralateral hemisphere at 3 and 14 days. A low density of glutamate receptors, the ability to sequester calcium by calcium-binding proteins and other hitherto unidentified factors may explain this relative resistance of interneurons to acute ischemia.

2-Amino-5-phosphonovalerate↗

PubMed1989

Selective neuronal vulnerability following transient cerebral ischemia in the gerbil: distribution and time course.

An important feature of ischemic brain damage is the selective vulnerability of specific neuronal populations. We studied the distribution and time course of neuronal damage following transient cerebral ischemia in the gerbil, using light microscopy and 45Ca autoradiography. Following 5 min of ischemia, selective neuronal damage determined by abnormal 45Ca accumulation was recognized only in the hippocampal CA1 subfield and part of the inferior colliculus. Ischemia for 10 to 15 min caused extensive neuronal injury in the 3rd and 5th layers of neocortex, the striatum, the septum, the whole hippocampus, the thalamus, the medial geniculate body, the substantia nigra, and the inferior colliculus. Progression of the damage was rapid in the medial geniculate body and the inferior colliculus, moderate in the neocortex, striatum, septum, thalamus, and the substantia nigra, and was delayed in the hippocampal CA1 sector. However, the delayed damage of the hippocampus occurred earlier when the ischemia period was prolonged. Histological observation revealed neuronal loss in the identical sites of the 45Ca accumulation. This study revealed that the distribution and time course of selective neuronal damage by ischemia proceeded with different order of susceptibility and different speed of progression.

Animals↗

PubMed1995

Selective neuronal vulnerability in the hippocampus--a role for gene expression?

Proposed mechanisms of neurodegeneration focus generally on the triggering of toxic biochemical pathways by an increased intracellular concentration of Ca2+. Recent evidence also suggests that Ca2+ causes transcriptional activation of so-called 'cell-death genes'. Efforts to elucidate the basis of selective vulnerability have relied on animal models of delayed neuronal death in the hippocampus. Biochemical and morphological data indicate that delayed neuronal death is a form of programmed cell death, or apoptosis. Observations that specific genes are activated transcriptionally for prolonged times in neuronal populations that are undergoing delayed death suggest that active gene expression is part of the neuronal-death cascade. Although a direct causal role remains to be proven, evidence implicates certain genes in neuronal-death pathways.

Animals↗

PubMed2001

Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria.

Parkinson's disease (PD) is a major cause of age-related morbidity and mortality, present in nearly 1% of individuals at ages 70-79 and approximately 2.5% of individuals at age 85. L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression. Association between mitochondrial dysfunction, monoamine oxidase (MAO) activity, and dopaminergic neurotoxicity has been repeatedly observed, but the mechanisms underlying selective dopaminergic neuron depletion in aging and neurodegenerative disorders remain unclear. We now report that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the MAO metabolite of dopamine, is more cytotoxic in neuronally differentiated PC12 cells than dopamine and several of its metabolites. In isolated, energetically compromised mitochondria, physiological concentrations of DOPAL induced the permeability transition (PT), a trigger for cell death. Dopamine was > 1000-fold less potent. PT inhibitors protected both mitochondria and cells against DOPAL. Sensitivity to DOPAL was reduced > or = 30-fold in fully energized mitochondria, suggesting that mitochondrial respiration may increase resistance to PT induction by the endogenous DOPAL in the substantia nigra. These data provide a potential mechanism of action for L-DOPA-mediated neurotoxicity and suggest two potentially interactive mechanisms for the selective vulnerability of neurons exposed to dopamine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Cell-Type-Specific Differences in Age-Related Changes of DNA Repair in the Mouse Brain - Molecular Basis for a New Approach to Understand the Selective Neuronal Vulnerability in Alzheimer's Disease.

Despite intensive research over the last decades, the molecular basis of the selective neuronal vulnerability in Alzheimer's disease (AD) is still largely unknown. In this context we have recently shown by means of quantitative autoradiography that presumably all types of neurons in the mouse brain suffer an age-related decrease in the rate of mitochondrial DNA synthesis, while in contrast only some distinct types of neurons showed a decrease in the rate of spontaneous overall nuclear DNA repair measured as unscheduled nuclear DNA synthesis. Most strikingly, there was a highly positive correlation to be found between that group of neurons in the mouse brain showing the age-related decrease in the rate of spontaneous overall nuclear DNA repair (pattern X) and the pattern of neurons in the human brain which - according to the literature - are affected by the formation of neurofibrillary tangles in AD (pattern Y). To minimize the risk that this correlation was a result of mere chance based on the selection of the nine types of neurons investigated thus far, in the present study nine further types of neurons in phylogenetically different regions of the mouse brain were investigated by using the same method. An age-related decrease in the rate of spontaneous overall nuclear DNA repair was found only for projection neurons of brain areas with a more plastic, variable and/or malleable structure over phylogenesis but neither for projection neurons of brain areas with a more rigid, invariant and/or conservative structure over phylogenesis nor for interneurons. The obtained results confirmed the highly positive correlation between the aforementioned patterns X and Y. Together with a wealth of data from the literature regarding age-related neuron loss in both the rodent and the human brain, these results may indeed indicate a new approach for understanding the selective neuronal vulnerability in AD.

Journal Article↗

PubMed1996

Copper/zinc superoxide dismutase expression in the human central nervous system. Correlation with selective neuronal vulnerability.

Oxidative stress has been implicated in the pathogenesis of several neurological disorders. We examined the regional distribution of copper/zinc superoxide dismutase (SOD-1), one of the key antioxidant enzymes, in the human central nervous system using in situ hybridization. Our results show that the enzyme is present at high levels of constitutive expression in alpha-motor neurons, oculomotor neurons, nucleus basalis, substantia nigra, neocortex, and the hippocampal sector resistant to hypoxia (H2). Relatively lower levels were found in Sommer's sector (H1) and Purkinje cells. We conclude that a lower constitutive level of SOD-1 expression may play a role in the selective vulnerability of certain neuronal populations to hypoxia but does not correlate with the patterns of neurodegeneration observed in amyotrophic lateral sclerosis. Parkinson's disease, and Alzheimer's disease.

Adult↗

PubMed1992

Postischemic binding of [3H]phorbol 12,13-dibutyrate and [3H]inositol 1,4,5-trisphosphate in the gerbil brain: an autoradiographic study.

Postischemic alteration of second messenger systems was investigated in the Mongolian gerbil, utilizing [3H]phorbol 12,13-dibutyrate and [3H]inositol 1,4,5-trisphosphate receptor autoradiography. Transient ischemia was induced for 10 min, and animals were allowed to survive for various recirculation periods of up to one month. [3H]Phorbol 12,13-dibutyrate binding in selectively vulnerable areas showed no significant change 1-24 h after ischemia except for a transient decline in a few regions. Thereafter, the binding in most of the selectively vulnerable areas showed significant alteration 48 h or seven days after ischemia. Interestingly, dentate molecular layer which was resistant to ischemia showed a significant elevation in the number of [3H]phorbol 12,13-dibutyrate binding sites. One month after ischemia, [3H]phorbol 12,13-dibutyrate binding showed significant reduction only in the striatum and the hippocampal CA1 sector where severe neuronal damage was seen morphologically. A significant elevation in the number of [3H]phorbol 12,13-dibutyrate binding sites was still seen in the dentate molecular layer one month after ischemia. In contrast, [3H]inositol 1,4,5-trisphosphate binding showed significant reduction in the selectively vulnerable regions 1-24 h after ischemia. Thereafter, [3H]inositol 1,4,5-trisphosphate binding in most of the selectively vulnerable areas markedly decreased up to one month after ischemia. In the dentate molecular layer, [3H]inositol 1,4,5-trisphosphate binding also showed significant reduction during recirculation except for a slight recovery 48 h and seven days after ischemia. One month after ischemia, the binding in all regions showed significant reduction. These results suggest that postischemic alteration of two second messenger (protein kinase C and inositol 1,4,5-trisphosphate) binding sites was produced with different processes in selectively vulnerable areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Ischemic stroke and incomplete infarction.

BACKGROUND: The concept of selective vulnerability or selective loss o f individual neurons, with survival of glial and vascular elements as one of the consequences of a systemic ischemic-hypoxic insult (eg, transient cardiac arrest or severe hypotension), has been recognized for decades. In contrast, selective neuronal death as one of the lesions that may develop in the brain after occluding an intracranial artery is an idea not readily acknowledged in the current medical literature dealing with human stroke. SUMMARY OF REVIEW: A review of pertinent publications reveals that selective neuronal injury after middle cerebral artery occlusion was observed in autopsy specimens over 40 years ago, although its pathogenesis remains unclear. Recent observations in both humans and animals suggest that selective neuronal necrosis (rather than infarct) is the consequence of either a short-term arterial occlusion or permanent occlusion accompanied by ischemia of moderate severity. During the acute and subacute states of an ischemic stroke, the loss of a limited number of neurons (ie, incomplete infarction) does not result in structural changes discernible by either CT or conventional MRI. However, the loss of a selected number of neurons may be demonstrable in vivo by calculating the corresponding loss of benzodiazepine receptors. The use of specific radiotracers in combination with single-photon emission CT or positron emission tomography allows demonstration of a decrease in gamma-aminobutyric acid-ergic receptor sites at places where many neurons have been lethally injured. CONCLUSIONS: We aim to alert physicians to the potential development of incomplete brain infarctions in patients with intracranial arterial occlusions. Recognizing incomplete infarcts is particularly important in the context of stroke therapy with thrombolytic and neuroprotective agents. This brain lesion is likely to be the consequence of an arterial occlusion with a resultant ischemia of moderate severity (eg, regional blood flows in the range of 15 to 20 mL x 100 g-1 x min-1).

Animals↗

PubMed2005

Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.

Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca(2+)-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca(2+)-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca(2+) buffers are valuable because they facilitate rapid relaxation times of Ca(2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca(2+) buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca(2+) disregulation and excitotoxic cell damage.

Amyotrophic Lateral Sclerosis↗

PubMed1992

Autoradiographic analysis of dopamine D1 receptors in the gerbil brain following transient cerebral ischemia.

1. We studied the postischemic time-course of dopamine D1 receptors in selectively vulnerable areas in the gerbil using receptor autoradiography. 2. [3H]SCH 23390 was used to label dopamine D1 receptors and transient cerebral ischemia was induced for 10 min. 3. [3H]SCH 23390 binding showed no significant alteration in selectively vulnerable areas at an early stage (1-24 hr) of recirculation. Thereafter, [3H]SCH 23390 binding showed a significant reduction in most selectively vulnerable areas 48 hr or 7 days of recirculation. The ventromedial striatum and dentate gyrus which were resistant to ischemia also exhibited a significant reduction in [3H]SCH 23390 binding. 4. Especially, marked reduction was noted in the dorsolateral striatum. However, this reduction in the dorsolateral striatum was not seen early in the recirculation prior to morphological neuronal damage. 5. The result suggests that transient cerebral ischemia can cause a severe reduction in dopamine D1 receptors in most selectively vulnerable areas. Furthermore, they suggest that dopamine D1 transmission is not always responsible for the evolution of ischemic brain damage. 6. These findings are discussed in relation to the mechanism of ischemic brain damage.

Animals↗

PubMed2005

Short-term effects of kainic acid on CA1 hippocampal interneurons differentially vulnerable to excitotoxicity.

PURPOSE: We sought to identify the inhibitory interneurons of the rat hippocampal CA1 region selectively vulnerable in the kainic acid (KA) model of temporal lobe epilepsy and to determine whether their selective vulnerability could be due to differential short-term KA effects. METHODS: We quantified vulnerable interneurons in stratum oriens-alveus (O/A) by using immunohistochemistry for glutamic acid decarboxylase (GAD), parvalbumin (PV), and somatostatin (SS) after KA injections in rats, and then compared in normal slices the effects of KA on interneurons either in O/A (vulnerable to KA) or in strata radiatum and lacunosum-moleculare (R/LM) (resistant to KA) by using whole-cell recording and calcium imaging. RESULTS: GAD-, PV- and SS-positive cells in O/A were decreased after KA treatment in P20 and P30 rats. Both short (1-min) and long (10-min) applications of KA produced similar tetrodotoxin (TTX)-insensitive membrane depolarization and decrease in input resistance in O/A and R/LM interneurons. KA responses were antagonized by CNQX and GYKI52466, suggesting AMPA receptor activation. KA also generated a similar increase in intracellular Ca2+ in O/A and R/LM interneurons, which was antagonized by CNQX and GYKI52466. CONCLUSIONS: The selective vulnerability of GAD-, PV-, and SS-immunopositive O/A interneurons in the KA model may not arise from cell-specific short-term membrane effects or calcium responses induced by KA, but from other glutamate receptor-mediated excitotoxic processes.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1999

Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases.

Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs. In this report we show uniform severe loss of PV+ neurons also in other TSEs such as GSS, kuru, new variant and familial CJD. In contrast, these neurons are mostly well preserved, or only moderately reduced, in FFI. Only PV+ neurons surrounded by isolectin-B4 positive perineuronal nets were severely affected in TSEs, suggesting a factor residing in this type of extracellular matrix around PV+ neurons as modulator for the selective neuronal vulnerability.

Adult↗

PubMed2000

AMPA receptor current density, not desensitization, predicts selective motoneuron vulnerability.

Spinal motoneurons are more susceptible to AMPA receptor-mediated injury than are other spinal neurons, a property that has been implicated in their selective degeneration in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether this difference in vulnerability between motoneurons and other spinal neurons can be attributed to a difference in AMPA receptor desensitization and/or to a difference in density of functional AMPA receptors. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. Single-cell RT-PCR quantification of the relative abundance of the flip and flop isoforms of the AMPA receptor subunits, which are known to affect receptor desensitization, did not reveal any difference between the two cell populations. Examination of AMPA receptor desensitization by patch-clamp electrophysiological measurements on nucleated and outside-out patches and in the whole-cell mode also yielded similar results for the two cell groups. However, AMPA receptor current density was two- to threefold higher in motoneurons than in dorsal horn neurons, suggesting a higher density of functional AMPA receptors in motoneuron membranes. Pharmacological reduction of AMPA receptor current density in motoneurons to the level found in dorsal horn neurons eliminated selective motoneuron vulnerability to AMPA receptor activation. These results suggest that the greater AMPA receptor current density of spinal motoneurons may be sufficient to account for their selective vulnerability to AMPA receptor agonists in vitro.

Animals↗

PubMed1990

Vacuolization, incubation period and survival time analyses in three mouse genotypes injected stereotactically in three brain regions with the 22L scrapie strain.

In previous studies we showed that C57BL mice injected stereotactically in the cerebellum with the 22L scrapie strain had a significantly shorter incubation period than those injected with the same agent in other brain regions. In mice injected in the cerebellum, vacuolization was limited to the cerebellum, medulla and mesencephalon, whereas injection into forebrain regions resulted in vacuolization in all brain regions. The studies suggested that the cerebellum had a selective vulnerability for 22L. In this study we examined the interaction between host genotype and selective vulnerability of specific brain regions. The mouse gene that has the most profound effect on pathogenesis, particularly incubation period, is termed Sinc (scrapie incubation). Groups of mice with three genotypes of Sinc (s7s7, p7p7 and their F1 cross, s7p7) were injected with 22L into the cerebral cortex, thalamus or cerebellum. Analysis of incubation periods showed that, regardless of the host genotype, the cerebellum injection group had a significantly shorter incubation period than groups injected in other regions. After cerebellum injection vacuolization was limited to the cerebellum, medulla and mesencephalon in all three host genotypes. The location of vacuoles within the cerebellum differed depending upon the host strain. Vacuolization developed almost exclusively in grey matter in s7s7 mice, mainly in white matter in p7p7 mice, and in both grey and white matter in F1 mice. These results demonstrate that the selective vulnerability of the cerebellum to induction of clinical disease by 22L does not depend on host genotype, but host genotype does affect lesion distribution within the cerebellum.

Animals↗

PubMed2000

Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampal neurons with reduced seizure vulnerability.

Selective hippocampal cell loss and altered neurotransmitter receptor expression have been proposed as pathogenic mechanisms in the development of chronic mesial temporal lobe epilepsy (TLE). Studies in animal models point to metabotropic glutamate receptors (mGluRs) as modulators of hippocampal epileptogenesis. In addition, mGluRs may constitute specific targets for the development of novel anticonvulsive drugs. As mGluR4 represents an inhibitory class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expression of mGluR4 in surgical hippocampal specimens obtained from patients with TLE by using immunohistochemistry and in situ hybridization. Although the hippocampi of control specimens (n = 11) were almost devoid of mGluR4 immunolabeling, all TLE specimens (n = 35) showed a striking up-regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus. Immunoelectron microscopy localized the receptor protein to the periphery of presynaptic and postsynaptic membranes. In situ hybridization revealed increased transcript levels of mGluR4 in dentate granule cells and residual CA4 neurons of TLE specimens compared with controls. Our results suggest a potential role of mGluR4 in counteracting excitatory hippocampal activity and in modulating seizure-associated vulnerability of hippocampal neurons. These data may also provide a basis for pharmacological studies of mGluR4 agonists as potential novel drugs in the treatment of TLE.

Adult↗