The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability
- Biol Psychiatry. 2019 Jun 15;85(12):1001-1010. doi: 10.1016/j.biopsych.2019.02.007.
- 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: [email protected].
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.