Pathogenetic basis of seizure susceptibility in a hamster model of cortical malformation

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2010～2012課題番号: 22591125研究代表者: 高野 知行（滋賀医科大学・医学部・准教授）興奮性の神経細胞障害による細胞内Ca2+の上昇は軸索の伸長や樹状突起の成長を阻害する。これは神経細胞の移動障害を惹起し、多小脳回症などの皮質形成異常の成因となる。トレーサーを用いた研究結果から、多小脳回の皮質形成過程には異常皮質領域への大脳基底核原基由来の抑制性神経細胞の細胞動員が関与し、皮質興奮性を修飾する。また、多小脳回症における抑制性の介在神経細胞の分布は不均一で外側の傍多小脳回領域に最も密に集積し、これによる興奮性および抑制性神経活動の不均衡が、本症におけるてんかん原性の発現に密接に関与する。Sustained elevation of the intracellular level of Ca2+ in response to glutamate receptor activation can result in depolymerization of microfilaments and microtubules, thus leading to dendritic outgrowth cessation and regression. These processes are suggested to be the primary mechanisms underlying the neuronal migration disorders and the resultant polymicrogyria observed in this experiment. A neuronal tracing study of progenitor cells in the ganglionic eminence using biotinylated dextran amine (BDA) demonstrated the interneurons to be mobilized to the microgyric area out of the ganglionic eminence, thus suggesting the development of new inhibitory neuronal connections after the onset of excitotoxic brain lesions. The lateral paramicrogyral area had the greatest number of parvalbumin-immunoreactive neurons, which was increased significantly in comparison to that in the control cortex (P < 0.01). We suggest that the callosal, thalamic and intracortical afferents to the microgyrus and paramicrogyral area may induce a remarkable imbalance between the excitatory and inhibitory activities of the cortical structures, associated with the epileptogenic mechanism in polymicrogyria