# Phasic dopamine and symptom domains of mental illness

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $540,999

## Abstract

Project Summary
Activity patterns in the brain establish the manner in which sensory information is perceived and salience and
valence are assigned. Disruptions of these patterns through genetic mutations are likely a major cause of
neurodevelopmental disorders and mental illness more broadly defined. The midbrain dopamine system plays
an essential role in salience and valence assignment and mutations within several ion channels known to
regulate action potential firing patterns by dopamine neurons have been identified in neurodevelopmental
disorders, yet virtually nothing is known of the impact of these mutations on dopamine physiology, circuit
function, and behavior. We have demonstrated that genetic inactivation of different genes associated with
mental illness can have differential effects on dopamine neuron physiology and phenotypic outcomes.
Neurodevelopmental disorders such as autism and schizophrenia are represented by a mosaic of phenotypic
outcomes that gives rise to the spectral nature of these disorders. Disruption of ion channel function, or
channelopathies are a major factor in disorder etiology. Of these, potassium channels are the most diverse
group and are among the most broadly implicated in channelopathies. Dopamine neurons express a suite of
voltage and non-voltage sensitive potassium channels that regulate the action potential waveform, synaptic
integration, and neurotransmitter release. Based on these diverse functions, we propose that elucidating the
physiological and phenotypic outcomes associate with a loss of function of these channels in dopamine
neurons will provide important insight into how disruption of these channels yields a mosaic of phenotypes. To
this end, we have developed a single viral vector-based system for the rapid mutagenesis of potassium
channels in dopamine neurons and demonstrated that inactivation of different channels yields both overlapping
and non-overlapping phenotypes in mice. The experiments proposed here will further elucidate common and
uncommon phenotypic outcomes and the impact of ion channels on the operation of distinct dopamine
subsystems.

## Key facts

- **NIH application ID:** 10116471
- **Project number:** 5R01MH104450-07
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** LARRY S ZWEIFEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $540,999
- **Award type:** 5
- **Project period:** 2015-03-04 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116471

## Citation

> US National Institutes of Health, RePORTER application 10116471, Phasic dopamine and symptom domains of mental illness (5R01MH104450-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10116471. Licensed CC0.

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