The goal of this proposal is to understand the interactions between the activity of a neural network and the properties of the synapses that link the individual neurons. The rationale for the proposed studies is based on several discoveries made during the last grant cycle. In area CA3 of the disinhibited hippocampal slice preparation, bursts of network activity are possible when there is sufficient strength of the recurrent collateral synapses that link the pyramidal cell in this area. Thus short-term, activity-dependent depression of the strength of these synapases terminates bursts, and recovery from this short-term depression determines when the next burst is possible. Further, long-term determinants of the strength of these synapses also affect burst probability, so that both long-term potentiation (LTP) and long-term depression (LTD) produce corresponding long-term changes in burst timing. Under the appropriate conditions, burst activity can induce either LTP or LTD. In the case of LTD, the changes in strength are stabilized by an associated change in the threshold for further LTP or LTD induction. In the next cycle we propose to test two hypotheses related to these findings. First, one component of short-term synaptic depression in CA3 appears to be mediated by dendritic calcium influx. We will test the hypothesis that adenosine acting at presynaptic A1 receptors mediates this unusual mechanism of short-term depression. Second, we will investigate the mechanism by which the threshold for long-term synaptic plasticity is altered in CA3. We will test the hypothesis that a reduction in the maximum NMDA receptor-mediated postsynaptic calcium influx is associated with LTD. Finally, we will test how these relationships between synaptic properties and network behavior may affect epileptogenesis and the treatment of seizures. These investigations will help us understand what determines the timing of interictal epileptic activity, which is needed in order to use the temporal pattern of interictal activity to predict the probability of future seizures. In addition, these investigations will help us understand how to produce stable, long-term decreases in the probability of seizures by selective induction of LTD at the most active synapses in epileptic foci.
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