Cytoskeletal Pathway: Exploring a New System for Treating Adolescent Depression

     Dr. Lauren Shapiro has a PhD in Molecular and Systems Pharmacology and is currently working in a fellowship at Loyola University Chicago. On November 19, she presented her research on her 2018 study titled Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice. Dr. Shapiro described the main purpose of the study, which was to explore effects of inhibiting Rho-kinase, a cytoskeletal regulatory factor, in adolescent mice who exhibited depression. Results demonstrated that Rho-kinase “ROCK” inhibition had anti-depressant like effect in the mice, with an efficacy comparable to the current antidepressants used, namely: ketamine and fluoxetine. The ROCK inhibitor, fasudil, also aided in dendritic pruning, which is crucial in adolescent depression. Moreover, the study presents a cytoskeletal pathway for a potential treatment for adolescent-onset depression.

     Dr. Shapiro’s talk and findings prove to be of high importance to the pharmacology and neuroscience field, as novel treatments are often sought for when treating mental illness. This is exemplified through the article Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid anti-depressant like activity in BALB/cj mice (2016). This article evaluates how the serotonergic system plays a role in the antidepressant-like effects of a ketamine dose in rodents. Ketamine and fluoxetine were compared to analyze patterns of antidepressant and anxiolytic responses. The main findings denoted that ketamine appears to be a more efficient antidepressant compared to fluoxetine, as several behavioral tests indicated. This was mainly due to neural adaptation of mPFC circuits differences in both drugs, which are likely to modulate the serotonergic characteristics of each. Researchers further state that ketamine blocks NMDA-R on GABA interneurons, which decreases GABAergic tone, and thus increases excitatory synaptic signaling and glutamate release in the mPFC.

     The results of the aforementioned study relate to Dr. Shapiro’s research in many ways. As described in Shapiro’s study, they utilize fasudil (the ROCK inhibitor) to accelerate pruning in a cytoskeletal pathway. This occurs at a dendritic level, where the drug targets the signaling ends of neurons in order to aid the ones prone to pruning, which will then give depressive effects. This is different from the 2017 study, which uses ketamine instead of fasudil, and targets neurons in the medial prefrontal cortex. Ketamine aids neurotransmitter release and increases synapse activation to give antidepressant-like effects. In other words, this study uses the neurotransmitter pathway, which is different than the cytoskeletal pathway described in Shapiro’s article.

The 2017 study investigates topics related to how the ketamine drug works in rodents’ brain and compares it to fluoxetine which is also commonly used for depression. But Shapiro’s research reaches a new dimension by taking both ketamine and fluoxetine and comparing the “classic” antidepressants to a possible new treatment, which is the fasudil drug. This is very innovative, as it explores a different take on how adolescent-onset depression can be treated looking away from the traditional manner of neurotransmitter targets.

    Certainly, both studies provide exceptional insight regarding depression treatment mechanisms. They shed light to how pharmacologic compounds work in the brain in order to produce positive effects that aid the negative effects of depression. Treatment options, whether from a neurotransmitter or cytoskeletal point of view, should be further studied for more insight on how to help this and other mood disorders.


Works cited 

Pham, T.H., Mendez-DAvid, I., Defaix, C., Guiard, B.P., Tritschler, L., David, D.J., & Gardier, A.M (2017). Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/jc mice. Neuropharmacology, 112, 198-209. Retrieved from http://cesp-2016.vjf.inserm.fr/wp-content/uploads/productions/Ha-ketamine-Neuropharmacology2016.pdf

Shapiro, L.P., Kietzman, H.W., Guo, J., Rainnie, D.G., & Gourley, S.L. (2019) Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice. Neurobiology of disease, 124, 520-530.