Cited by 101Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior

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Fox, Megan E., Chandra, Ramesh, Menken, Miriam S., Larkin, Emily J., Nam, Hyungwoo, Engeln, Michel, Francis, T. Chase, Lobo, Mary Kay·2020·Molecular Psychiatry

Abstract

Depression alters the structure and function of brain reward circuitry. Preclinical evidence suggests that medium spiny neurons (MSNs) in the nucleus accumbens (NAc) undergo structural plasticity; however, the molecular mechanism and behavioral significance is poorly understood. Here we report that atrophy of D1, but not D2 receptor containing MSNs is strongly associated with social avoidance in mice subject to social defeat stress. D1-MSN atrophy is caused by cell-type specific upregulation of the GTPase RhoA and its effector Rho-kinase. Pharmacologic and genetic reduction of activated RhoA prevents depressive outcomes to stress by preventing loss of D1-MSN dendritic arbor. Pharmacologic and genetic promotion of activated RhoA enhances depressive outcomes by reducing D1-MSN dendritic arbor and is sufficient to promote depressive-like behaviors in the absence of stress. Chronic treatment with Rho-kinase inhibitor Y-27632 after chronic social defeat stress reverses depression-like behaviors by restoring D1-MSN dendritic complexity. Taken together, our data indicate functional roles for RhoA and Rho-kinase in mediating depression-like behaviors via dendritic remodeling of NAc D1-MSNs and may prove a useful target for new depression therapeutics.

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Authors
Fox, M. E., Chandra, R., Menken, M. S., Larkin, E. J., Nam, H., Engeln, M., Francis, T. C., & Lobo, M. K.
Affiliations
University of Maryland, Baltimore (US)
Corresponding author
Lobo, Mary Kay
Venue
Molecular Psychiatry
Published
2018-08-17
Volume
25
Issue
5
Pages
1022-1034
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
OpenAlex
W2885753453
Cited by
100
References
76
Citations by year
2026: 9 · 2025: 7 · 2024: 12 · 2023: 10 · 2022: 16 · 2021: 19 · 2020: 18 · 2019: 8 · 2018: 1
FWCI
7.42
Type
journal article
Language
en
Open access
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH106500, F32MH116574)
  • One Mind/ Janssen Rising Star Translational Research Award
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
depression, RhoA, Rho kinase, dopamine D1 receptor, medium spiny neurons, nucleus accumbens, dendritic remodeling, dendritic atrophy, social defeat stress, social avoidance, Y-27632, structural plasticity, reward systems
MeSH terms
Animals, Dendrites, Depression, Male, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Nucleus Accumbens, Receptors, Dopamine D1, Receptors, Dopamine D2, rhoA GTP-Binding Protein, Mice, rho-Associated Kinases

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