Grant: Research Tools and Instruments - Category 1 (<$150,000)

Intercellular communication between nerve cells in the brain involves highly specialized regions of contact,termed synapses, between pre and post-synaptic neurons. It is here that there is an enrichment of receptors and signaling molecules that respond to neurotransmitters and growth factors that, in turn, can strengthen and/or weaken a particular synapse. The increase and/or loss of particular synapses underlies a process termed neuronal plasticity and it is this process that modulates neuronal activity and the process of learning and memory. Two different classes of cell surface receptors have been shown to serve important roles in learning and memory. First, the NMDA receptors which are activated by excitatory neurotransmitters in the brain (eg. glutamate) and, second, a receptor termed TrkB which responds to a growth factor termed brain-derived neurotrophic factor (BDNF). Since these are 2 very different types of receptors, it is not well understood how they co-regulate this process. My lab has identified 2 intracellular signaling molecules that regulate the activity of both receptors, namely, the adapter protein ShcC and the nucleotide exchange factor, RasGrf1. ShcC-/- mice are smarter, learn faster and have increased levels of tyrosine phosphorylation of the NR2B subunit of the NMDA receptor. This uncouples the receptor from clathrin-mediated turnover and increases its cell surface expression and potential for activation. We have found that ShcC can interact with a tyrosine phosphatase, possibly STEP, and potentially regulate its localization to the post synaptic membrane to de-phosphorylate NR2B. RasGrf1, on the other hand, binds to the NMDA receptor and decreases NMDA signaling and synaptic activity. We have found when TrkB is activated, RasGrf1 is uncoupled from the NMDA receptor. This increases NMDA signaling and the activation of Erk which positively correlates learning and memory. We will continue to use molecular approaches to characterize these interactions and their effect(s) on synaptic growth and NMDA receptor signaling in wild type, ShcC-/- and RasGrf1-/- mice.