Grant: CIHR Fellowship

Activity-dependent changes of synaptic efficacy are the cellular basis of learning and memory. Synaptic plasticity bidirectionally modifies synaptic strength by enhancing or depressing transmission, effected through a complexity of mechanisms that act pre- and postsynaptically, over different time scales, and in response to different stimuli. Despite decades of intensive research, the fundamental question of how changes in synaptic efficacy are ultimately expressed during plasticity remains to be unequivocally answered; that is, to what extent and over what timescales do plasticity events modify respectively presynaptic neurotransmitter release and the number or function of postsynaptic receptors? This outstanding question represents a fundamental gap in our knowledge about how synaptic plasticity is evoked to modify the function of neuronal networks controlling behaviour. The rapid and dynamic regulation of AMPA-type glutamate receptor (AMPAR) surface mobility constitutes a major mechanism underlying synaptic plasticity. However, it is also apparent that the recruitment or removal of AMPARs by exo- and endocytotic mechanisms postsynaptically, and changes in neurotransmitter release probability presynaptically, are also involved in synaptic modulation during plasticity. Here, I propose to use a multi-level approach combining electrophysiology, genetically-encoded optical reporters, innovative molecular tools to control AMPAR trafficking, and state-of-the-art super-resolution imaging approaches to determine how the dynamics of AMPAR surface mobility postsynaptically, and synaptic vesicle release presynaptically, define the functional properties of synaptic transmission during both basal and plastic states. This work will shed new light on the fundamental mechanisms of synaptic transmission, plasticity and specificity, and advance our knowledge of the etiology of numerous psychiatric, neurological and neurodegenerative disorders that are linked to AMPAR dysregulation.