The goal of this research is to understand the physiological mechanisms by which excitation and inhibition in the hippocampus can be modulated over relatively short time periods based on patterns of activation of the synapse. It is our hypothesis that the differential modulation of excitatory and inhibitory synaptic efficacy is responsible, at least in part, for the transition between relatively stable interictal activity and seizures and for the spread of seizure activity from areas of focal abnormality to normal areas of CNS. By increasing our understanding of these processes, it is hoped that new strategies for preventing or treating epilepsy will be developed. These experiments will be carried out in a new preparation of very low density dissociated cultures of rat hippocampal neurons. Recording will be made with whole cell patch clamp electrodes from single neurons and from isolated pairs of synaptically connected neurons. The synaptic interactions between the neurons will also be analyzed with histological techniques. The properties of miniature synaptic potentials, both mini- EPSCs and mini-IPSCs, will be examined and it will be determined if they behave as predicted by the quantum hypothesis. Changes in mini-psc amplitude, shape or frequency will be used to help determine if frequency dependent changes in synaptic efficacy are due to presynaptic or postsynaptic factors. Once this is determined, the mechanisms involved will be ascertained. The following hypotheses will be directly tested: (1) Excitatory and inhibitory synapses between hippocampal neurons behave differently when activated at moderate or high frequencies. (2) Neurotransmitter release characteristics are substantially different for excitatory and inhibitory synapses under comparable physiological conditions. (3) Synaptic transmission between hippocampal neurons in culture can be described by the quantum hypothesis. (4) Frequency dependent decrement in inhibitory synaptic efficacy is due predominantly to presynaptic mechanisms. (5) Frequency dependent increment in excitatory synaptic efficacy is due partially to presynaptic mechanisms. (6) Changes in postsynaptic receptor properties may contribute to the frequency dependent effects and this is more prominently involved in the increment of excitatory synaptic function. At the end of these experiments, the mechanisms which underlie frequency- dependent potentiation of excitatory synapses and decrement of inhibitory synapses will be better understood. It will then be possible to extrapolate these findings to an appropriate epilepsy model (a slice preparation or animal model) to test the hypothesis that these changes in synaptic efficacy are responsible in whole, or in part, for the transition to seizures in an epileptogenic area and for the spread of seizure activity from a seizure focus to normal areas of cortex. Using selective methods for preventing or reversing these effects, it is hoped that, ultimately, seizures can be prevented or suppressed.
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