DESCRIPTION: (Applicant's Abstract) The pre- and postsynaptic processes underlying long-term potentiation and depression (LTP and LTD) have been the focus of more than two decades of extensive research and debate. We recently demonstrated that induction of LTD between a pair of neurons within an isolated "triplet circuit" of hippocampal neurons in culture results in long-lasting changes in synaptic strength at non-activated synapses of the triplet circuit. The spread of LTD to neighboring synapses following induction of LTD at glutamatergic synapses was more extensive than following induction at GABAergic synapses. Two critical questions arise from these findings: (1) what is the cellular mechanism underlying the spread of plasticity to non-activated synapses, and (2) is "propagated plasticity" a different and additional form of activity-dependent modification to the extensively studied "induced plasticity"? The goal of this application is to describe and develop this larger picture of synaptic plasticity, to gain an understanding of the distributed effects of activity on the efficacy of synapses in a simplified network of neurons in vitro. Simultaneous patch-clamp recordings from two to four synaptically interconnected neurons in culture will allow examination of changes in efficacy of synaptic connections between the different neurons following induction of LTD and LTP. Specific Aim 1 is to extend our previous findings on the spread of LTD, to examine the distributed effects of the induction of LTP on non-activated synapses in the simple circuits of cultured hippocampal neurons. Specific Aim 2 will determine the cellular mechanism underlying the spread of synaptic plasticity. Specific Aim 3 will examine whether an individual neuron integrates induced and propagated plasticity from activity within the local circuit. An understanding of the fundamental principles governing the distributed activity-dependent modifications of synapses in local neural circuits will be vital to the understanding of the mechanisms of learning, memory, various aspects of mental health, and the pathogenesis of neurological and aging disorders such as epilepsy and Alzheimer's disease.