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

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.

Cell Adhesion Factors in the Orbitofrontal Cortex Control Cue-Induced Reinstatement of Cocaine Seeking and Amygdala-Dependent Goal Seeking

“…3B). To confirm that fasudil did not generally suppress protein levels, we next immunoblotted for trkB, which is elevated by ROCK inhibition in the mPFC (Shapiro et al, 2019). Fasudil increased vlOFC levels, as expected (unpaired t (38) = À2.3, p = 0.03, d =À0.74; Fig.…”

“…), dissolved in sterile saline. The dose was selected because it can improve certain forms of learning and memory and trigger cortical dendritic spine plasticity (DePoy et al, 2017;Swanson et al, 2017;Hinton et al, 2019;Shapiro et al, 2019).…”

Semaphorin3F Drives Dendritic Spine Pruning Through Rho-GTPase Signaling

“…One possibility is that inhibition of Rap1 by Sema3F [12] compromises activation of Rap-dependent RhoGAPs, such as ARAP3 or p190RhoGAP [58,60,61], favorable for RhoA activation. It should be noted that Rac1 and RhoA pathways have shown differential effects in promoting or inhibiting spine retraction [39,[62][63][64]. These differences may be due to different ligands, sustained versus acute ligand stimulation [65], or developmental timing.…”

Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

“…The copyright holder for this preprint this version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.05.433425 doi: bioRxiv preprint 3 0 should be noted that Rac1 and RhoA pathways have shown differential effects in promoting or inhibiting spine retraction [62][63][64]39]. These differences may be due to different ligands, sustained versus acute ligand stimulation [65], or developmental timing.…”