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.

Public Health Relevance

Discrete neuronal activity patterns define how information is processed in the brain. The manner in which disruption of these patterns by disease-associated mutations impacts behavioral regulation is poorly understood, but likely contributes to the etiology of many symptom domains of mental illness. We will use advanced genetic techniques coupled with in vivo and ex vivo electrophysiology and behavior to establish how distinct potassium channels implicated in neurodevelopmental disorders impact dopamine neuron physiology and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104450-07
Application #
10116471
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rossi, Andrew
Project Start
2015-03-04
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Guo, Nannan; Soden, Marta E; Herber, Charlotte et al. (2018) Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. Nat Med 24:438-449
Locke, Timothy M; Soden, Marta E; Miller, Samara M et al. (2018) Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. Biol Psychiatry 84:401-412
Jo, Yong S; Heymann, Gabriel; Zweifel, Larry S (2018) Dopamine Neurons Reflect the Uncertainty in Fear Generalization. Neuron 100:916-925.e3
Chung, Amanda S; Miller, Samara M; Sun, Yanjun et al. (2017) Sexual congruency in the connectome and translatome of VTA dopamine neurons. Sci Rep 7:11120
Geisheker, Madeleine R; Heymann, Gabriel; Wang, Tianyun et al. (2017) Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci 20:1043-1051
Gore, Bryan B; Miller, Samara M; Jo, Yong Sang et al. (2017) Roundabout receptor 2 maintains inhibitory control of the adult midbrain. Elife 6:
G├╝ler, Ali D; Rainwater, Aundrea; Parker, Jones G et al. (2012) Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. Nat Commun 3:746