The overall objective of the proposed studies is to understand the activities generated by the large neuronal network in the hippocampus. Our studies address the long-standing question in cortical neurophysiology and EEG concerning how a population of interconnected neurons can general rhythmical extracellular waves. Such activities, arising from synchronized oscillations of neuronal populations, are observed in vivo (theta rhythm, epilepsy) and in vitro. Our experiments have focused on defining functional parameters, including cell excitability and synaptic strengths, that determine the amplitude and frequency of rhythmic activities. Recent results have allowed us to hypothesize the role of synaptic inhibition in synchronized population discharges. The proposed studies will characterize the physiology and pharmacology of the inhibitory circuit in the CA3 region of the hippocampus. The circuit primarily involves local GABAergic neurons. In vitro experiments will be carried out to address three major issues. These are: (1) The mode of synaptic activation of local inhibitory neurons. (2) Physiology and morphology of inhibitory neurons, and (3) properties of postsynaptic GABA receptors and ipsp's produced by inhibitory neurons. Our recent studies showed that inhibitory function was suppressed following tetanic stimulation leading to population oscillation in the CA3 region; the proposed experiments will allow us to identify potential modifiable sites within the inhibitory circuit. Experiments will be carried out using simultaneous intracellular recordings in the CA3 region of the hippocampal slice and patch-clamp recordings of dissociated adult hippocampal cells. Using the slice preparation, inhibitory neurons will be identified directly by their action on postsynaptic cells and they will be marked by intracellular fluorescent dye to allow correlation of physiology and morphology. Patch-clamping of dissociated hippocampal cells will be used primarily to examine postsynaptic receptors activated by GABA, the major inhibitory transmitter in the hippocampus. The generator mechanism of the synchronized oscillations we examine in the hippocampus is directly relevant to that underlying interictal discharges recorded n some simple forms of epilepsy. Thus the proposed experiments will provide information on both normal and abnormal operations of the hippocampus.
