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Neurobiol Dis. 2019 Apr;124:520-530. doi: 10.1016/j.nbd.2018.12.015. Epub 2018 Dec 26.

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice.

Author information

1
Molecular and Systems Pharmacology, Emory University, Atlanta, GA, United States; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States; Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States.
2
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States; Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States; Graduate Program in Neuroscience, Emory University, Atlanta, GA, United States.
3
Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States; Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, United States.
4
Molecular and Systems Pharmacology, Emory University, Atlanta, GA, United States; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States; Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States; Graduate Program in Neuroscience, Emory University, Atlanta, GA, United States; Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, United States. Electronic address: shannon.l.gourley@emory.edu.

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.

KEYWORDS:

Forced swim; HA-1077; Novelty suppressed feeding; Protein kinase B; ROCKII; Rho-associated coiled-coil containing kinase; Slx-2119

PMID:
30593834
PMCID:
PMC6365018
[Available on 2020-04-01]
DOI:
10.1016/j.nbd.2018.12.015

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