The regulation of inhibition in mammalian cortex is intimately involved with the development and control of epilectic events. An understanding of the factors which modulate inhibition could lead to the development of improved methods for treating epilepsy. This grant proposes to study the physiological and pharmacological processes which underlie normal synaptic inhibition in mammalian cortex, employing dissociated cell cultures of mammalian neocortex and hippocampus as model systems. The currents responsible for inhibition generated by GABA, the inhibitory neurotransmitter, will be analyzed using whole cell patch clamp and single electrode voltage clamp techniques. The Cl channel which GABA activates will be characterized, using gigaseal patch clamp techniques. The mechanism which underlies desensitization of the GABA response will be determined at the level of whole cell currents and single channels. Drugs which interact with the GABA receptor complex and other antiepileptic drugs will be examined for their effects on IPSPs, and their mechanisms of action at the level of channel kinetics will be determined. In addition, the mechanisms by which several cortical neuropeptides (SOM, CCK, VIP, ENK) act to modulate synaptic inhibition will be examined and their effects on channel kinetics will be determined. Other """"""""inhibitory"""""""" currents in the cortical neurons, especially Ca activated K and Cl currents, which may play important roles in the control of epileptogenic processes, will be examined. The channels underlying these currents will be characterized. The """"""""plasticity"""""""" of these events in relation to repetitive activation and the ability of drugs or neuropeptides to modulate these events will also be determined. It is hoped that an increased understanding of the physiological and pharmacological regulation of synaptic and non-synaptic inhibition in mammalian cortex will contribute toward the development of improved strategies for treating epilepsy.
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