ABSTRACT
Temporal lobe epilepsy (TLE) is the most common type of human epilepsy and has been related with extensive loss of hippocampal pyramidal and dentate hilar neurons and gliosis. Many characteristics of TLE are reproduced in the pilocarpine model of epilepsy in mice. This study analyzed the neuronal damage, assessed with Fluoro-Jade (FJB) and cresyl violet, and gliosis, investigated with glial fibrilary acidic protein (GFAP) immunohistochemistry, occurring in the hippocampal formation of mice at 3, 6, 12 and 24h, 1 and 3 weeks after the pilocarpine-induced status-epilepticus (SE) onset. The maximum neuronal damage score and the FJB-positive neurons peak were found in the hilus of dentate gyrus 3 and 12 h after SE onset (P<0.05), respectively. At 1 week after SE onset, the greatest neuronal damage score was detected in the CA1 pyramidal cell layer and the greatest numbers of FJB-positive neurons were found both in the CA1 and CA3 pyramidal cell layers (P<0.05). The molecular, CA3 and CA1 pyramidal cell layers expressed highest presence of GFAP immunoreaction at 1 and 3 weeks after SE onset (P<0.05). Our findings show that, depending on the affected area, neuronal death and gliosis can occur within few hours or weeks after SE onset. Our results corroborate previous studies and characterize short time points of temporal evolution of neuropathological changes after the onset of pilocarpine-induced SE in mice and evidences that additional studies of this temporal evolution may be useful to the comprehension of the cellular mechanisms underlying epileptogenesis.
Subject(s)
Gliosis/etiology , Hippocampus/pathology , Nerve Degeneration/etiology , Status Epilepticus/pathology , Analysis of Variance , Animals , Cell Death/drug effects , Disease Models, Animal , Disease Progression , Fluoresceins , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Hippocampus/physiopathology , Male , Mice , Movement Disorders/etiology , Muscarinic Agonists/toxicity , Organic Chemicals , Pilocarpine/toxicity , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Status Epilepticus/chemically induced , Time FactorsABSTRACT
Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at theta=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.
Subject(s)
Epilepsy, Temporal Lobe/genetics , Genetic Linkage/genetics , Hippocampus , Potassium Channels, Voltage-Gated/genetics , Atrophy/genetics , Atrophy/physiopathology , Epilepsy, Temporal Lobe/physiopathology , Genotype , Hippocampus/pathology , Hippocampus/physiopathology , HumansABSTRACT
Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at theta=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.
Canais de potássio voltagem-dependentes (CPVD) desempenham importante papel na excitabilidade neuronal e estão associados a determinados tipos de epilepsia. Recentemente, um tipo de encefalite límbica autoimune (EL) foi associado com anticorpos contra CPVD. Além disso, há relatos de pacientes com EL e epilepsia parcial, além de hipersinal em regiões límbicas detectadas em imagens de ressonância magnética (IRM). Nós temos descrito a epilepsia de lobo temporal mesial familial (ELTMF) associada à atrofia hipocampal (AH) e outros sinais de esclerose mesial temporal observadas em IRM. Para investigar se os CPVD podem estar associados com a AH identificada na ELTMF, empregamos o estudo de ligação genética nesses genes candidatos. Setenta e três marcadores microssatélites foram genotipados e o LOD score de dois pontos mostrou Zmax variando de 0.11 a -9.53 para teta=0.00. No presente estudo, os dados obtidos com a análise de ligação mostram que os CPVD não estão envolvidos na determinação da AH na ELTMF.
Subject(s)
Humans , Epilepsy, Temporal Lobe/genetics , Genetic Linkage , Hippocampus , Potassium Channels, Voltage-Gated/genetics , Atrophy/genetics , Atrophy/physiopathology , Epilepsy, Temporal Lobe/physiopathology , Genotype , Hippocampus/pathology , Hippocampus/physiopathologyABSTRACT
A transgenic mouse model carrying a mutation in the Scn2a gene showed chronic focal seizures associated with extensive cell loss and gliosis in the hippocampus, a similar phenotype found in familial mesial temporal lobe epilepsy (FMTLE). Our objective was to test whether the human homolog of the Scn2a gene is responsible for hippocampal abnormalities in FMTLE by linkage analysis. We conclusively ruled out the SCN2A gene as candidate in FMTLE.
Subject(s)
Epilepsy, Temporal Lobe/genetics , Nerve Tissue Proteins/genetics , Sodium Channels/genetics , Temporal Lobe/pathology , Genetic Linkage , Humans , Microsatellite Repeats , Mutation , NAV1.2 Voltage-Gated Sodium Channel , SclerosisABSTRACT
Os efeitos de múltiplos status epilepticus induzidos pela pilocarpina no período precoce pós natal foram avaliados na vida adulta. Para tanto, animais que apresentaram SE consecutivos no 7§, 8§ e 9§ dias de vida foram submetidos a testes comportamentais (esquiva inibitória, caixa de Skinner, rota-rod, campo aberto e o labirinto em cruz elevado), ao registro eletrográfico com 30, 60 e 90 dias de vida e posteriormente a análise histológica. Somente em 4 animais foram observadas crises espontâneas isoladas durante o período de observação (lOO dias). Os registros eletrográficos mostraram a ocorrência de vários episódios de espículas e/ou poliespículas que apareciam no hipocampo e cortex. O estudo comportamental demonstrou aumento da atividade exploratória, comprometimento no aprendizado. A análise histológica não revelou a presença de necrose neuronal, entretanto em PN10 observamos que os corpos apoptóticos já presentes na formação hipocampal do grupo controle eram muito mais evidentes no grupo experimental. Nossos resultados demonstram que a ocorrência de múltiplos SE nos períodos iniciais da vida promovem um aumento da morte neuronal por apoptose e evidentes alterações eletrográficas, déficits cognitivos e raros episódios de crises espontâneas na vida adulta mesmo na ausência dano neuronal
