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.
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
Biol Psychiatry. 2019 Jun 15;85(12):1001-1010. doi: 10.1016/j.biopsych.2019.02.007. Epub 2019 Feb 13.
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.
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.
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.
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.
伏隔核多巴胺 1 型受体中间神经元（D1-MSN）在小鼠抑郁样行为的发展中起着关键作用。社会挫败应激通过早期生长反应 3（EGR3）和 Rho 鸟苷三磷酸酶 RhoA 的表达和激活导致这种 MSN 亚型的树突形态发生变化。然而，尚不清楚 RhoA 抑制如何影响应激诱导易感性的基础电生理特性。
使用新型 RhoA 特异性抑制剂 Rhosin 抑制慢性社会挫败应激后 RhoA 的活性。进行 D1-MSN 的全细胞膜片钳电生理记录，以评估 Rhosin 处理对应激小鼠突触和内在的影响。此外，还对记录的细胞进行填充和形态学分析。
我们发现 RhoA 抑制可预防社会挫败应激引起的 D1-MSN 过度兴奋和兴奋性传入至 D1-MSN 的减少。伏隔核特异性 RhoA 抑制能够阻断 D1-MSN EGR3 表达引起的易感性。最后，我们发现 Rhosin 增强了棘突密度，这与 D1-MSN 的兴奋性相关，而不影响整体树突分支。
这些发现表明，应激期间 RhoA 的药理学抑制可驱动伏隔核神经元中一组总棘突数量的增加，从而防止与应激相关的电生理缺陷，并促进应激恢复力。
