Neuronal excitability is determined by a complex interaction of intrinsic voltage sensitive ion channels with extrinsic inhibitory and excitatory influences. There is evidence to suggest that epilepsy, a pathologic state of neuronal hyperexcitability, may involve abnormalities between individual elements in inter-related cellular aggregates, so called """"""""local circuits"""""""". However, technical limitations preclude a cellular analysis of isolated cellular interactions in situ. The proposed research is designed to characterize the anatomic and physiologic properties of a mammalian model system (hippocampus in dissociated cell culture) and then use this system to investigate excitatory and inhibitory local circuit interactions. Hippocampal neurons will be identified in several ways. A regional identification of CA3-CA4 neurons will be made on the basic of retrograde labelling of commissural projections with fluorescent dyes. These and un-labelled neurons will be further characterized morphologically by a detailed analysis of dendritic and axonal processes. Each cellular morphology will be correlated with active and passive membrane properties. Synaptic transmission between identified will be studied with regard to the functional sign of the synapse and basic properties of transmission. A quantal analysis of release characteristics will be performed. The differential modulatioin of excitatory and inhibitory synapses to repetitive activation will be explored and mechanism examined. The pharmacology of excitatory and inhibitory neurotransmission will be defined with specific antagonists.
