Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice.
Neurobiol Dis
; 124: 520-530, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30593834
ABSTRACT
Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression.
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Base de dados:
MEDLINE
Assunto principal:
Córtex Pré-Frontal
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1-(5-Isoquinolinasulfonil)-2-Metilpiperazina
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Quinases Associadas a rho
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Antidepressivos
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Plasticidade Neuronal
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article