FGF13 Control of Hippocampal Excitability in Cocaine Contextual Memory

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Project Summary Overdose deaths caused by cocaine use disorder (CUD) pose a major public health burden in the United States due in part to a lack of pharmacological treatments. The hippocampus is a major brain region for forming and maintaining drug associated contextual memories. Pharmacologically disrupting these associations, in supplement with existing psychosocial treatments, can potentially reduce the health risks of CUD. My proposal is driven by this critical need to identify novel molecular mechanisms underlying hippocampal regulation of cocaine seeking behavior. My preliminary findings suggest a role for voltage-gated sodium channels (VGSCs) in supporting cocaine contextual memory, via regulation by the VGSC auxiliary subunit Fibroblast Growth Factor 13 (FGF13). I discovered that fibroblast growth factor homologous factor 13 (FGF13) is expressed in a subset of nNOS+ interneurons. Deletion of FGF13 from this subset of hippocampal interneurons results in increased cocaine conditioned place preference (CPP). I aim to define the roles of FGF13 in controlling hippocampal excitability and subsequent role in cocaine contextual memory. I hypothesize that FGF13 plays a critical role in the formation of cocaine-contextual memory by regulating VGSC function and consequent neuronal excitability of a subset of nNOS+ hippocampal interneurons. I will address this hypothesis through the following Specific Aims: Aim 1: To define FGF13 maintenance of sodium channel excitability in hippocampal interneurons. Aim 2: To test FGF13 sufficiency in mediating cocaine contextual memory acquisition and extinction. To perform these experiments, I will use a floxed FGF13 mouse line generated by our lab to record electrophysiological properties of FGF13+ hippocampal interneurons (Aim 1) in response to cocaine exposure as well as to evaluate the role of FGF13 in mediating cocaine contextual memory (Aim 2). My fellowship training plan outlines the steps I will take to gain technical expertise in slice electrophysiology (Aim 1), for which I have little prior experience, and to employ viral tools in studying mouse models of addiction (Aim 2), which are also techniques that are new to me. The research environment in the Neuroscience Graduate Program at Weill Cornell Medicine is well suited for me to complete my goals. The proposed experiments will help establish a model by which FGF13 controls hippocampal excitability, and enhance our understanding of contextual memory and drug addiction overall. The objective of this proposal is to identify FGF13 as a novel pharmacological target for treating cocaine dependence.