Synaptic plasticity, the molecular process thought to underlie learning and memory, allows neurons to modulate the strength and number of their synapses in response to activity. Key mediators of this process are the N-methyl-D-aspartic acid (NMDA)-type glutamate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), both of which initiate signaling cascades critical for plasticity. At many synapses, NMDAR and mGluR signaling mediate plasticity by controlling the trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), ligand gated ion channels responsible for the majority of fast excitatory neurotransmission. The number and subunit composition of AMPARs dramatically affects the excitatory properties of a synapse, thereby regulating synaptic strength. Although their role in effecting change in AMPAR localization has been well described, the mechanisms by which mGluR and NMDAR signaling govern AMPAR trafficking remain incompletely understood. The proposed research will characterize a novel downstream target of glutamatergic signaling, protein kinase D1 (PKD1), and elucidate the pathway's importance in modulating protein trafficking at the synapse.
Specific Aim 1. Elucidate the mechanisms by which PKD1 regulates GluR2 trafficking.
Specific Aim 2. Characterize the functional significance of PKD1 regulation of GluR2 trafficking. Elucidating the cellular mechanisms behind memory formation is critical to understanding the dysfunction and loss of memory in neurological disease. Although it is known that neurons can alter their connections in response to experience, and that this process underlies learning and memory, how neurons achieve such changes is not wholly understood.
This research aims to investigate how neurons regulate the sensitivity of their connections in response to neuronal activity.
