The Selective RhoA Inhibitor Rhosin Promotes Stress Resiliency Through Enhancing D1-Medium Spiny Neuron Plasticity and Reducing Hyperexcitability
Open accessAbstract
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.
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Reduced dendritic complexity is associated with reduced excitatory input but increased intrinsic excitability.
“Reduced dendritic complexity largely agrees with changes in other brain regions [151, 152] and is associated with reduced excitatory input but increased intrinsic excitability [88, 89], which may reflect homeostatic self-tuning [153].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [89]
The mechanism underlying structural plasticity of MSNs in CSDS is altered expression and activity of Rho GTPases.
“The mechanism underlying structural plasticity of MSNs in CSDS is altered expression and activity of Rho GTPases [88, 89, 138, 141].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [89]
Spine density is unchanged in D1-MSNs.
“Spine density is unchanged in D1-MSNs [88, 89], yet there is evidence MSNs from susceptible mice have more stubby spines [156].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [89]
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Research works printed but not linked: 2
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- Authors
- Francis, T. C., Gaynor, A., Chandra, R., Fox, M. E., & Lobo, M. K.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Lobo, Mary Kay
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 85
- Issue
- 12
- Pages
- 1001-1010
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC7368664
- OpenAlex
- W2913064755
- Cited by
- 61
- References
- 48
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 12 · 2019: 4
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH106500, F32MH116574)
- National Institute on Drug Abuse (R01DA038613)
- National Institute of General Medical Sciences Postdoctoral Research Associate (1FI2GM128622-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- RhoA inhibition, dopamine D1 receptor, nucleus accumbens, medium spiny neurons, social defeat stress, stress resilience, EGR3, dendritic spine density, neuronal hyperexcitability, synaptic plasticity, depression-like behavior
- MeSH terms
- Animals, Male, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Nucleus Accumbens, Organic Chemicals, Stress, Psychological, Receptors, Dopamine D1, rhoA GTP-Binding Protein, Early Growth Response Protein 3, Resilience, Psychological
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