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.

Grant Number: 5K00MH133250-06
NIH Institute/Center: NIH
Principal Investigator: Noële Certain