Active Cl- Homeostasis Hypothesis and the Experimental Models of Epilepsy

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  • Fukuda Atsuo
    Department of Physiology, Hamamatsu University School of Medicine

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  • 能動的Ｃｌ｀－´ホメオスタシス仮説と実験的てんかん病態モデル
  • 能動的Cl－ホメオスタシス仮説と実験的てんかん病態モデル

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Abstract

One of the recent topics in neuroscience is that the major inhibitory neurotransmitter GABA necessarily evokes excitation in immature brain, in contrast to inhibition in normal adult brain. Such excitatory GABA actions may be involved in neural circuitry development promoted by neuronal differentiation, migration, and synaptogenesis. On the other hand, a conversion of GABA response from inhibition to excitation could also be induced by certain pathological condition even in adult. Since GABAA receptor is a Cl- channel, such a developmental or a pathological switch of GABA action between inhibition (Cl- influx) and excitation (Cl- efflux) is induced by changes in Cl- gradient. We have been investigating the dynamics of neural functions modulated by such active Cl- homeostasis in the experimental models of epilepsy.<br> Tetanic stimulation induced post-tetanic depolarization followed by seizure-like afterdischarge in hippocampal CA1 neurons in brain slices. Massive Cl- influx during tetanic stimulation was responsible for [Cl-]i increases lasting for the period of afterdischarge. This acute postsynaptic Cl- accumulation through GABAA receptor channels via feed-forward inhibition resulted in reversal of its own action to excitation. This feed-forward excitation induced a seizure-like afterdischarge, implicating a relation with epileptogenesis. The neuronal Cl- homeostasis is regulated by cation-Cl- cotransporters, so that the active shift of Cl- homeostasis could be generated by the dynamic balance of Cl- importer (NKCC1) and exporter (KCC2). In a rat kindling model, there was an activity-dependent increase in NKCC1 mRNA in the dentate gyrus and the pyriform cortex. Thus an increase in [Cl-]i and a reduction in GABAergic inhibition may occur in those epileptic rats. In a rat neonatal cortical freeze-lesion model of human polymicrogyria, GABA-induced depolarizations associated with increases in [Cl-]i were observed in cortical plate neurons migrating into the dysplastic lesion. NKCC1 mRNA was upregulated whereas KCC2 mRNA was downregulated in those migrating neurons. These characteristics were similar to the known characteristics of migrating cortical plate cells. Thus, cortical plate cells locating adjacent to the necrotic center of the freeze-lesion might regain or preserve the excitatory GABA actions, so that they could migrate into the dysplastic lesion to form microgyrus. Thus a collapse of active Cl- homeostasis may be responsible for a pathogenesis of both idiopathic and organic epilepsies.<br>

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