Impact of Trio Insufficiency on Cholinergic Development and Function

PROJECT SUMMARY The regulation of the number and composition of AMPA receptors is a critical feature in maintaining brain function. AMPA receptor regulation has been implicated in numerous brain disorders including drug addiction, a disorder that affects more than 20 million patients in the US alone. AMPA receptors are glutamate-gated ion channels, responsible for the process of learning and memory, and dysregulation can lead to reinforcement of additive behaviors. AMPA receptors are associated with diverse auxiliary subunits. These auxiliary subunits regulate both AMPA receptor functional activity expression at synapses. Mechanisms of how auxiliary subunits regulate AMPA receptor expression are poorly understood. I have preliminary data indicating that a class of auxiliary subunits, called cornichon homologs, regulate AMPA receptor assembly, specifically the transition from receptor dimers into functional tetramers (Aim 1). I will evaluate human AMPA receptor variants associated with neurodevelopmental disorders that potentially disrupt auxiliary subunit interactions and affect receptor assembly (Aim 2). To evaluate receptor biogenesis and trafficking, I will take a novel approach by dual tagging AMPA receptors and their auxiliary subunits to identify intracellular changes. I will also measure changes to synaptic transmission and plasticity due to loss of AMPA receptor - auxiliary subunit interactions. Results from these aims will provide insights into the intracellular processing of AMPA receptors and potential avenues for therapeutic targets. The knowledge I gain in neurobiology and acquired techniques from the F99 Phase will be essential for my transition into a postdoctoral position in neuroscience. For the K00 Phase, I plan to pursue training in a laboratory focused on in vivo electrophysiology and imaging to investigate the process of drug addiction in rodent models (Aim 3). The ultimate goal of this proposal is to learn innovative techniques to investigate changes at the molecular and organismal level and to develop the expertise and independence to become an neuroscientist.