GABA-ergic inhibitory postsynaptic potentials (IPSPs) in the mammalian central nervous system can profoundly affect the input-output relationships for neurons. IPSPs in the hippocampus and the deep cerebellar nucleus are of major importance in the regulation of epileptic activity and in motor coordination, respectively. In hippocampal CA1 neurons in which Ca2+ is chelated or protein kinase C activity suppressed, a tetanic stimulation of the stratum radiatum induces long-term potentiation (LTP) of the IPSPs. The effects of high frequency presynaptic activity on IPSPs in the deep cerebellar nucleus are, however, unknown. The objectives of the proposal are to understand the mechanisms involved in the LTP of IPSPs in hippocampal CA1 neurons and to examine tetanus-mediated changes in IPSPs in the deep cerebellar nucleus. Current- as well as voltage-clamp techniques will be used to record IPSPs and IPSCs from CA1 neurons in the guinea pig hippocampus and neurons in the rat deep cerebellar nucleus, in brain slice preparations. The following are the specific aims for studies on the hippocampal CA1 neurons: (1) to examine the involvement of specific receptors (GABA-A, GABA-B, NMDA, AMPA, metabotropic glutamate receptors) in the induction of long-term potentiation (LTP) of the IPSPs; (2) to determine the modulation of the LTP by (a) changes in [Ca2+]i (through dihydropyridine-sensitive or NMDA receptor-coupled channels, or through intracellular release), (b) second messengers (PKC, CaM kinase II, NO), and (c) the postsynaptic membrane potential; and (3) to elucidate the presynaptic mechanisms involved in the LTP. The following are the specific aims for the studies on neurons of the deep cerebellar nucleus: (1) to examine the participation of GABA-A and GABA-B receptors in the IPSPs; (2) to determine the short- and long-term effects of tetanic stimulations on the IPSPs and, if changes occur, to elucidate the mechanisms involved (shifts in the EIPSP, pre- or post- synaptic locus, GABA-A or GABA-B receptor activation, changes in [Ca2+]i and other intracellular second messengers, and the influence of the postsynaptic neuronal membrane potential). It is anticipated that a knowledge of the modulation of high frequency activity-mediated changes in the IPSPs will contribute to an improved understanding of the mechanisms of cellular learning & memory, cerebellar control of motor coordination, and the regulation and treatment of epileptic activity.
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