Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior.
Mol Psychiatry
; 25(5): 1022-1034, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-30120419
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Dopamina D1
/
Proteína rhoA de Ligação ao GTP
/
Dendritos
/
Depressão
/
Quinases Associadas a rho
/
Plasticidade Neuronal
Limite:
Animals
Idioma:
En
Revista:
Mol Psychiatry
Assunto da revista:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos