Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential

Stephanie C Gantz; Maria M Ortiz; Andrew J Belilos; Khaled Moussawi

doi:10.7554/eLife.64241

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Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential

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Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential

Stephanie C Gantz, Maria M Ortiz, Andrew J Belilos and Khaled Moussawi

eLife, Vol.10, e64241

04/06/2021

DOI: 10.7554/eLife.64241

PMCID: PMC8024007

PMID: 33822716

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https://doi.org/10.7554/eLife.64241View

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Abstract

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM -GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM -GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM -GlyR with the uPSEM ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs and in vitro as indicated by cell-attached recordings from D1-MSNs in mouse brain slices. Whole-cell recordings showed that activation of PSAM -GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM -GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. These data show that 'inhibitory' PSAM -GlyR chemogenetics may activate certain cell types and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

Neuroscience

mouse

uPSEM

chemogenetics

PSAM

D1 medium spiny neuron

chloride permeability

Details

Title: Subtitle: Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential
Creators: Stephanie C Gantz - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States
Maria M Ortiz - Biological and Biomedical Neuroscience Program, University of North Carolina, Chapel Hill, United States
Andrew J Belilos - National Institute on Drug Abuse, Baltimore, United States
Khaled Moussawi - Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, United States
Resource Type: Journal article
Publication Details: eLife, Vol.10, e64241
DOI: 10.7554/eLife.64241
PMID: 33822716
PMCID: PMC8024007
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: England
Grant note: DA048085 / NIDA NIH HHS
Language: English
Date published: 04/06/2021
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984071701302771

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