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Biol Psychiatry. 2019 Jun 15;85(12):1001-1010. doi: 10.1016/j.biopsych.2019.02.007. Epub 2019 Feb 13.

The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability.

Author information

1
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland; Synaptic Plasticity Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
2
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
3
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: mklobo@som.umaryland.edu.

Abstract

BACKGROUND:

Nucleus accumbens dopamine 1 receptor medium spiny neurons (D1-MSNs) play a critical role in the development of depression-like behavior in mice. Social defeat stress causes dendritic morphological changes on this MSN subtype through expression and activation of early growth response 3 (EGR3) and the Rho guanosine triphosphatase RhoA. However, it is unknown how RhoA inhibition affects electrophysiological properties underlying stress-induced susceptibility.

METHODS:

A novel RhoA-specific inhibitor, Rhosin, was used to inhibit RhoA activity following chronic social defeat stress. Whole-cell electrophysiological recordings of D1-MSNs were performed to assess synaptic and intrinsic consequences of Rhosin treatment on stressed mice. Additionally, recorded cells were filled and analyzed for their morphological properties.

RESULTS:

We found that RhoA inhibition prevents both D1-MSN hyperexcitability and reduced excitatory input to D1-MSNs caused by social defeat stress. Nucleus accumbens-specific RhoA inhibition is capable of blocking susceptibility caused by D1-MSN EGR3 expression. Lastly, we found that Rhosin enhances spine density, which correlates with D1-MSN excitability, without affecting overall dendritic branching.

CONCLUSIONS:

These findings demonstrate that pharmacological inhibition of RhoA during stress drives an enhancement of total spine number in a subset of nucleus accumbens neurons that prevents stress-related electrophysiological deficits and promotes stress resiliency.

KEYWORDS:

Intrinsic excitability; Medium spiny neuron; Nucleus accumbens; RhoA; Social defeat stress; Stress resilience

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