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

> **NIH NIH F32** · UNIVERSITY OF WASHINGTON · 2022 · $72,018

## Abstract

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.

## Key facts

- **NIH application ID:** 10384357
- **Project number:** 1F32MH129003-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Christopher W. Tschumi
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,018
- **Award type:** 1
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10384357

## Citation

> US National Institutes of Health, RePORTER application 10384357, Resolving the impact of a human KCNQ3 mutation on mesostriatal dopamine connectivity and striatal network dynamics in social behavior (1F32MH129003-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10384357. Licensed CC0.

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