Resolving the impact of a human KCNQ3 mutation on mesostriatal dopamine connectivity and striatal network dynamics in social behavior

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Project Summary Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), have complex etiologies and a diversity of phenotypic outcomes. A growing body of evidence implicates deficits in mesostriatal circuitry as contributing to several aspects of behavioral dysregulation associated with these disorders. Underlying these circuit-level dysfunctions, alterations in the brain-wide function of specific ion channels is emerging as a key factor in the etiology of NDDs. A variety of missense mutations in ion channels are found in individuals with NDDs. Many of these mutations occur in genes encoding potassium channels that are among the most diverse regulators of neuronal function, contributing to nearly every aspect of neuronal activity pattern regulation and neurotransmitter release dynamics. The Kv7 family of voltage-gated potassium channels encoded by KCNQ genes are increasingly linked to NDDs including ASD. These channels regulate neuronal excitability and are highly expressed in neurons of the mesostriatal circuitry of the brain. Within this pathway, network activity in the ventral striatum and its inputs from the ventral tegmental area (VTA) which release the neurotransmitter dopamine, regulate numerous behaviors that fall within the symptom domains of several NDDs. Collectively, these data point to Kv7 channels and the mesostriatal system as a potentially critical convergence point that warrants further investigation. It remains unclear how specific ion channels that contribute to mesostriatal circuit regulation impact these network dynamics. Under physiological conditions, Kv7 channels inhibit dopamine neurons, but the Kv7 regulation of excitability is complex. Mutations in all three arginine (R) residues that constitute the gating charges in the S4 transmembrane voltage sensor of KCNQ3 have been identified in NDD and ASD probands. The KCNQ3(R230C) mutant has been the best characterized and results in a gain of function increase in potassium conductance. I hypothesize that KCNQ3(R230C) decreases VTA dopamine neuron activity, resulting in dysregulation of ventral striatum network dynamics and associated dopamine- mediated social behavior. This research training plan will ensure that I master the necessary skill sets in: genetic manipulation of neural circuits, in vivo calcium imaging in freely moving mice, computational analysis, mouse social behavior paradigms, project management, written and oral communication, funding procurement, and mentorship necessary to become an excellent independent researcher.