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

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

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1022-1034
Number of pages13
JournalMolecular Psychiatry
Issue number5
StatePublished - May 1 2020

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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