ABSTRACT Neuropsychiatric disorders are thought to arise from complex changes of brain plasticity. Recent evidence points toward ion channel complexes as cellular hubs of plasticity that confer disease vulnerability or protection depending on the channel regulatory state. In medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a subtype of highly vulnerable cells, neuroadaptive changes in intrinsic firing are mediated by neurotrophin brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling. Yet, the molecular mechanisms by which these changes occur are still poorly understood. Intrinsic firing in MSN relies on the integrity of the macromolecular complex of the voltage-gated Na+ (Nav) channel Nav1.6 and its accessory regulatory fibroblast growth factor 14 (FGF14) and is subject to regulation by glycogen synthase kinase 3 (GSK3) β, a downstream effector of BDNF/TrkB signaling. Here, we provide exciting new evidence for the Nav1.6, FGF14 and GSK3β as a macromolecular signaling complex downstream of BDNF/TrkB critical for MSNs neuronal plasticity. Using an array of in vitro and in cell assays, cell imaging, and electrophysiology, we show that stability, phosphorylation and functional activity of the Nav1.6 channel are proportional to the level of BDNF and the kinase activity, whereby low level of BDNF predicts resilience and high level mediates a susceptible phenotype conferred by changes in neuron firing. We will conduct a full range of biophysical, biochemical and electrophysiological studies combined with pharmacological and viral vector-based in vivo gene transfer methods to evaluate the impact of BDNF/TrkB signaling on macromolecular composition (Aim 1), subcellular targeting (Aim 2) and functional properties (Aim 3) of the Nav1.6 channel in the context of neuroadaptive plasticity of MSNs. Outcomes of these studies could potentially lead to the development of biomarkers of susceptibility to neuropsychiatric disorders by investigating molecular pathways in relevant experimental models, an area of great interest for biological psychiatry.

PUBLIC HEALTH RELEVANCE Innovative and integrated approaches are needed to further understanding the basic mechanisms underlying neuronal plasticity that contribute to the pathophysiology of neuropsychiatric disorders, and thereby enable future development of effective therapeutic interventions. Through a multidisciplinary project including biophysics, molecular biology, biochemistry, imaging and single cell electrophysiology in rodent experimental models, we will identify novel bio-signatures of neuron vulnerability to disease based on neurotrophin-mediated regulation of the voltage-gated Na+ channel.