# Targeted mutagenesis to elucidate the function of understudied ion channels in the central nervous system

> **NIH NIH R03** · UNIVERSITY OF WASHINGTON · 2020 · $155,500

## Abstract

Project Summary/Abstract
Many types of neurons utilize complex and highly specific patterns of action potential firing to regulate
neurotransmitter release and communicate with downstream cells. Action potential firing is primarily regulated
through neurotransmitter input as well as through the expression of ion channel genes that determine the
baseline firing properties of an individual neuron. While some of these ion channels are well studied, many
remain unexplored or underexplored. Dopamine neurons in the ventral tegmental area (VTA) exhibit tightly
controlled activity patterns, including bursts and pauses in activity, which encode information about
environmental cues and rewards and influence learning and motivation. It is believed that disruptions in these
firing patterns contribute to a variety of behavioral perturbations associated with mental illness. Thus, VTA
dopamine neurons provide an excellent model system for investigating the function of understudied ion
channels within their native neuronal environment. A recent study identified the entire complement of ion
channels expressed in dopamine neurons in mice; I have selected for study three of these channels that also
appear on the Illuminating the Druggable Genome (IDG) list of understudied proteins: Cacna2d3, encoding the
2-3 calcium channel auxiliary subunit, Kcna6, encoding the Shaker potassium channel KV1.6, and Kcnab2,
encoding the KV2 potassium channel auxiliary subunit. I will utilize a novel, single vector adeno associated
viral system that takes advantage of CRISPR/Cas9 gene editing technology to rapidly induce gene mutation in
a cell-type specific (Cre-dependent) manner in neurons of adult mice. I will then use slice electrophysiology
and fast-scan cyclic voltammetry in combination with optogenetics to characterize the effects of individual ion
channel gene knockout and determine how these understudied ion channels regulate dopamine neuron
physiology and dopamine release dynamics. Completion of this research will establish a simple, single virus
technique for rapidly and specifically inducing gene knockout, which will be widely applicable to investigations
of understudied proteins. Additionally, by identifying novel regulators of dopamine firing patterns we will both
increase our understanding of the underlying physiology driving these critical neurons and identify new
potential targets for precision therapeutics.

## Key facts

- **NIH application ID:** 10045757
- **Project number:** 1R03TR003307-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Marta E Soden
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $155,500
- **Award type:** 1
- **Project period:** 2020-08-15 → 2022-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045757

## Citation

> US National Institutes of Health, RePORTER application 10045757, Targeted mutagenesis to elucidate the function of understudied ion channels in the central nervous system (1R03TR003307-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10045757. Licensed CC0.

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