Knowledge of the principles that govern activity-dependent neural plasticity is integral to understanding both normal and impaired memory function. The overall goal of the studies proposed here is to examine the prerequisite conditions and underlying mechanisms of homosynaptic long-term depression (LTD) at the commissural-CA1 synapse in the hippocampus in vivo. Homosynaptic LTD is a lasting decrease in synaptic transmission that results from activity in the afferent pathway. Research with formal models of learning and memory has shown that synaptic strength must have the capacity to both decrease and increase in a use-dependent manner for successful simulation of these cognitive processes. Research with forebrain synapses maintained in vitro has demonstrated that homosynaptic LTD does occur, that its induction is favored when excitatory synaptic activation occurs during hyperpolarization or attenuated depolarization of the postsynaptic cell, and that its induction requires elevation of postsynaptic calcium levels. Little is known about the induction and expression of homosynaptic LTD in forebrain in vivo. Recent experiments with the commissural-CA1 synapse in the intact hippocampus have shown that robust LTD is induced at that synapse by stimulation of the commissural afferents with pairs of pulses using an interstimulus interval (ISI) that causes inhibition of CA1 pyramidal cell firing evoked by the second pulse of a pair. No LTD develops when the ISI is lengthened and pyramidal cell firing evoked by the second pulse is not inhibited, or when the calcium- permeable N-methyl-D-aspartate (NMDA) receptors is blocked. To gain further insights into the mechanisms by which paired-pulse stimulation induces LTD, the first study proposed here will assess the degree of correlation between paired-pulse inhibition and the induction of LTD. The second study will explore the mechanism that underlies paired-pulse inhibition; a likely candidate is feedforward and recurrent inhibition from local interneurons, because of the nature of the interconnectivity between interneurons and pyramidal cells. The third study will determine whether or not the contribution of this mechanism is required for the induction of LTD by paired-pulse stimulation. To enable analysis of contributing mechanisms at he single-cell level, the fourth study will serve to develop a protocol for studying LTD induced by paired-pulse stimulation in the hippocampal slice preparation. Using this protocol, the final study will examine whether or not the induction of LTD by paired-pulse stimulation requires postsynaptic calcium, as is suggested by the phenomenon's dependence on NMDA receptor activation. Collectively, the findings obtained from these studies will enhance our understanding of the neural processes that underlie learning and memory.
