Molecular and synaptic mechanisms of neurotrophin-glutamate crosstalk

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PROJECT SUMMARY Synaptic transmission and its plasticity are based on a core group of synaptic receptors that rapidly sense neurotransmitters such as glutamate and GABA. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are typically thought to signal on slower time scales, but have also been shown to regulate the induction and expression of synaptic plasticity. Despite both neurotransmitter and neurotrophin signaling underlying most forms of synaptic plasticity and serving as major mediators of the pathophysiology and treatment of neurogenerative and neuropsychiatric disorders, little is known about how these different receptor classes work in concert through direct and indirect forms of crosstalk. Motivated by the paucity of direct tests of neurotrophin/neurotransmitter crosstalk, our preliminary studies have indicated that the neurotrophin receptor, TrkB, and metabotropic glutamate receptor 5 (mGluR5) are able to mutually regulate each other in both native and heterologous systems. In contrast to previous studies which have focused on the ability of GPCRs to activate RTK signaling, we have identified one of the first examples of an RTK (TrkB) engaging a GPCR (mGluR5) as a signaling effector. In this proposal, we will test the hypothesis that mGluR5 is a critical mediator of TrkB effects by amplifying and altering the spatiotemporal dynamics of downstream signaling to canonical effectors to drive a unique form of crosstalk-dependent synaptic plasticity. Collectively, this new form of TrkB-mGluR5 signaling may contribute to the diverse higher order nervous system functions related to neural plasticity that have been attributed to the BDNF-TrkB neurotrophin system. Aim 1 will define BDNF-TrkB receptor mediated signaling crosstalk with mGluR5. Aim 2 will decipher the signaling mechanisms that regulate TrkB/mGluR5 crosstalk. Aim 3 will determine the impact of TrkB-mGluR5 synergy on BDNF-LTP and mGluR5-LTD.