Short- and Long-Term Proteomic Changes in Dendritic Spines Induced by Psychedelic Compounds with Therapeutic Applications

Psychedelic drugs, which act on the serotonin-2a receptor, have recently generated interest as potential novel treatments for substance use and mood disorders. A single dose of psilocybin confers antidepressant effects lasting for several months in humans and rodent studies have demonstrated that psilocybin induces structural plasticity in the prefrontal cortex on a timescale which appears to correlate with its antidepressant effects. Causal manipulations of dendritic spine formation can occlude the rapidly acting antidepressant effect for other novel antidepressants like ketamine, suggesting its necessity. Despite great interest in this area, there continue to be fundamental questions about how these spines may integrate into circuits to produce therapeutic effects. Understanding how dendritic spines form and persist in response to rapidly acting antidepressants may facilitate the utilization of these compounds as therapeutics for substance use disorders and could lead to development of pharmacological strategies that prolong their therapeutic effects.

Interestingly, the duration of drug effects on plasticity may not correlate with duration of psychedelic effects. We have demonstrated that even a drug which elicits very brief psychedelic effects can lead to long-term structural plasticity. Using, in vivo two-photon dendritic spine imaging, we have shown that the psychedelic compound 5-methoxy-DMT (5-MeO-DMT) enhances spinogenesis for >1 month after a single dose. In contrast, prior studies have demonstrated that the rapidly acting antidepressant ketamine only enhances spinogenesis for up to 1 week, which correlates with the duration of antidepressant effects. The goal of this study is to investigate the synaptic proteome of newly generated and persistent spines after administration of psychedelics with differing temporal effects on plasticity. We propose to do so using a novel approach via proximity labeling of synaptic proteins in collaboration with Dr. Angus Nairn and the NIDA Proteomics Center. This pilot study will enable us to identify targets for future functional studies testing the necessity of these identified proteins in spinogenesis. Future studies will couple these proximity labeling approaches and findings with in vivo two photon imaging of neural structure and second messenger systems in order to identify spatiotemporal events in therapeutic spinogenesis.