In normal immature cortical regions, synaptically-mediated inhibition is weak (compared to the normal adult), and develops relatively slowly. As the major inhibitory neurotransmitter in mammalian cortical structures, Gamma-aminobutyric (GABA) must plan an important role in determining the level of excitability of this tissue. Many studies of epilepsy have demonstrated that blockade of GABA-mediated inhibition can lead to epileptiform activity. Further, there appears to be a decrease of GABA terminals in chronic epileptic foci. Since the brain does appear to be particularly seizure prone at some early stages of development, it would be of interest to know whether and how such seizure susceptibility relates to the development of GABA-mediated inhibition. We will explore this question by correlating data from intracellular recordings in rabbit hippocampal neurons (in vitro slices) with thresholds for seizure generation in intact, maturing animals. In the process, we propose to study mechanisms for seizure onset, using the hippocampal slice as a simplified model system. Spontaneous and evoked seizure-like spreading depression and after discharge are generated in slices from immature rabbit hippocampus. Particular attention will be given to the role of inhibitory postsynaptic potentials (IPSPs) as the protective process which maintains cells at a hyperpolarized level and limits spread of excitability. In addition, the influence of extracellular potassium on PSPs and cellular excitability will be evaluated, and the contribution of the Na+, K+ ATPase pump studied. In parallel studies, we will focus on the development of the GABA/GAD (glutamic acid decarboxylase - the GABA synthesizing enzyme) system. Using electrophysiologic and pharmacologic techniques, we will study the development of IPSP potency and GABA efficacy in hippocampal neurons. Localization of GABA/GAD in local circuit neurons will be studied using GAD immunocytochemistry. These studies will yield information about the normal development of major control systems in hippocampus, and relate the efficacy of these systems to seizure susceptibility during development. Such data should also provide us with clues about how seizures develop - and might be controlled - in the maturing nervous system.
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