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The Rho‐kinase inhibitor, fasudil, has antidepressant‐like efficacy in adolescent mice
Author(s) -
Shapiro Lauren,
Gourley Shan
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.663.7
Subject(s) - fasudil , behavioural despair test , rho associated protein kinase , dendritic spine , antidepressant , prefrontal cortex , rho kinase inhibitor , mirtazapine , neuroscience , pharmacology , psychology , medicine , chemistry , kinase , biology , hippocampus , microbiology and biotechnology , cognition , hippocampal formation
Adolescence represents a critical period of neurodevelopment, defined by structural reorganization and synaptic maturation within the prefrontal cortex. Although these processes are critical for the transition to adulthood, structural instability may open a window of vulnerability to neuropsychiatric disorders including depression. Interventions that facilitate activity‐dependent neural remodeling, as occurs during adolescence, may be advantageous. Here we evaluated the therapeutic‐like potential of Rho‐kinase (ROCK) inhibition, which can expedite activity‐dependent dendritic spine plasticity. The brain‐penetrant ROCK inhibitor fasudil had antidepressant‐like effects in the forced swim test in adolescent mice and was comparable to ketamine and fluoxetine. Fasudil also decreased the latency to approach a palatable food in the novelty suppressed feeding task, a rapid antidepressant‐like effect. Within the adolescent ventromedial prefrontal cortex (vmPFC), fasudil increased levels of the post‐synaptic marker PSD‐95, while pruning dendritic spines, resulting in adult‐like spine densities. Fasudil stimulated several neurotrophin‐related signaling factors in the vmPFC, including increasing the ratio of full‐length:truncated tyrosine kinase receptor B (TrkB). Subsequent experiments utilizing viral vector‐based and pharmacological manipulations indicated, however, that the antidepressant‐like actions of fasudil are nonetheless attributable to the inhibition of the neuronal ROCK isoform, ROCK2. Support or Funding Information This work was supported by F31MH109208, Children's Healthcare of Atlanta, the Molecular and Systems Pharmacology Training Grant 5T32GM008602‐17, the Katherine Deschner Family NARSAD Award and a BRAINS Award: MH101477. The Yerkes Center is supported by the Office of Research Infrastructure Programs/OD P51OD011132. The Emory Viral Vector Core is supported by P30NS055077.