Depression of GABAergic inhibitory postsynaptic potentials (IPSPs) represents an important regulatory mechanism in mammalian brain. The present project will test the hypothesis that postsynaptic increases in intracellular calcium concentration ([Ca2+]i) resulting from physiological processes in hippocampal pyramidal cells depress GABAA IPSPs. Current-clamp and whole-cell voltage-clamp recordings will be made in the hippocampal slice preparation. The following specific aims are proposed: 1) To determine if increased [Ca2+]i in pyramidal cells depresses GABAA responses and GABAergic IPSPs and IPSCs. Preliminary data suggest that this is true. 2) To determine which of several possible sources of Ca2+i are effective in doing so. Voltage-dependent Ca2+ channels, ligand-gated Ca2+ influx, Ca2+ release from intracellular stores and ion exchange mechanisms will be investigated. 3) To identify the intracellular biochemical system or systems responsible for the Ca2+ effects. 4) To investigate the short- and long-term functional implications of the Ca2+ effect. Regulation of GABAergic IPSPs by Ca2+i implies that an important positive feedback interaction may exist between the GABAA system and the mechanisms of Ca2+ influx (e.g., voltage-dependent Ca2+ channels, NMDA- mediated responses, etc.) often influenced, directly or indirectly, by this system. This work is directly relevant for understanding the neurophysiology of epilepsy and of hippocampal long-term potentiation.
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