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

• Main Authors: Lauren P. Shapiro, Henry W. Kietzman, Jidong Guo, Donald G. Rainnie, Shannon L. Gourley
• Format: Article
• Language: English
• Published: Elsevier 2019-04-01
• Series: Neurobiology of Disease
• Subjects: Forced swim; Novelty suppressed feeding; Protein kinase B; HA-1077; ROCKII; Slx-2119
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996118303851

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.