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

• Type of Material: Article
• Authors: Lauren P. Shapiro, Emory University; Henry W. Kietzman, Emory University; Jidong Guo, Emory University; Donald Rainnie, Emory University; Shannon Gourley, Emory University
• Language: English
• Date: 2019-04-01
• Publisher: Elsevier Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2018.12.015
• Title of Journal or Parent Work: Neurobiology of Disease
• Volume: 124
• Start Page: 520
• End Page: 530
• Grant/Funding Information: This research project was also supported in part by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077, and by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; The work in the SLG lab was supported by NIH 5T32GM008602–17, F31MH109208, R01MH101477 and R01MH117103.; Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.; The work in the DGR lab was supported by NIH MH072908.; The Yerkes National Primate Research Center was supported by the Office of Research Infrastructure Programs/OD P51 OD011132.
• Keywords: Slx-2119; Forced swim; Brain; Mouse; Rapid antidepressant; Science & Technology; Fasudil; Depression; Neurosciences & Neurology; Life Sciences & Biomedicine; ROCKII; Neurosciences; Molecular mechanisms; Novelty suppressed feeding; Cytoskeletal; Rho-associated coiled-coil containing kinase; HA-1077; Activation; Protein kinase B; Prefrontal cortex; Children
• Research Categories: Biology, Molecular; Chemistry, Pharmaceutical; Biology, Neuroscience; Psychology, Psychobiology

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.