Two complementary approaches, one empirical and the other modeling, are being used to investigate the ways in which synaptic plasticity emerges from interactions among pre- and postsynaptic processes (e.g., presynaptic spike broadening, mobilization and depletion of transmitter, modulation of exocytosis, desensitization of postsynaptic receptors, and modulation of the numbers of transmitter receptors and transporters). The proposed studies will focus on the glutamatergic sensorimotor synapses that mediate withdrawal reflexes of Aplysia. Empirical studies, which are funded by NIH grant NS19895, characterize the biochemical and biophysical processes that underlie homo- and heterosynaptic plasticity. The modeling studies, which will be funding by the present proposal, will use these empirical data, and those in the published literature, to develop mathematical models of the synapse. The models will be manipulated to study the contributions of component processes to synaptic function and to identify critical parameters that warrant additional experimental examination. Particular attention will be focused on analyzing the responses of the synapse to brief bursts of presynaptic activity. Such bursts closely resemble the physiological responses of sensory neurons to test stimuli that are typically used in behavioral studies. Moreover, it has recently become clear that the traditional means of probing the synapse with a single presynaptic spike fails to reveal the full extent of modulatory processes that regulate synaptic efficacy. The proposed modeling studies will examine synaptic function and plasticity at multiple levels of organization, ranging from kinetic models of transmitter binding to receptors and transporters, to cellular models of synaptic transmission, to neural network models of presynaptic sensory neurons and a postsynaptic motor neuron. The specific aims of this project are: 1) Investigate the ways in which desensitization of glutamate (GLU) receptors and increases in the numbers of GLU transporters and receptors contribute to modulation of the PSP during brief bursts of presynaptic activity. 2) Investigate the relative contributions of pre- and postsynaptic processes to homo- and heterosynaptic modulation of the PSP during brief bursts of presynaptic activity. 3) Investigate the input-output relationship (i.e., the ability of presynaptic activity to drive the postsynaptic spiking) of the sensorimotor synapse during brief bursts of presynaptic activity.