PSILOCYBIN RESTORES HIPPOCAMPAL LTP AND ENHANCES AMPA RECEPTOR CURRENTS IN PYRAMIDAL CELLS: IMPLICATIONS FOR TREATMENT-RESISTANT DEPRESSION

Despite its high lifetime prevalence of 16-20%, depression often remains unresponsive to standard treatments, leaving a large number of patients with treatment-resistant depression. Psilocybin, a psychedelic compound, has shown promising results in clinical trials as a fast-acting antidepressant for treatment-resistant depression, with effects lasting up to one year following a single dose. However, the underlying molecular mechanisms of action remain largely unclear. A better understanding of these mechanisms could facilitate the development of targeted therapies.
Electrophysiological measurements were performed using the patch-clamp technique. EPSPs, AMPA receptor currents, and NMDA receptor currents were measured in hippocampal pyramidal cells and interneurons of the mouse. Naive and chronically stressed mice (CDM), representing a depression-like phenotype, were used. Either vehicle control, psilocybin at increasing concentrations, or psilocybin combined with various receptor antagonists were added to the artificial cerebrospinal fluid (ACSF).
Psilocybin significantly increased AMPA receptor currents in pyramidal cells, with this effect being activity-independent and persisting even after one hour of washout. EPSPs showed a significant increase compared to baseline, and EPSP amplitude correlated with AMPA receptor current amplitude. No significant changes in AMPA receptor currents were observed in interneurons, and NMDA receptor currents remained unaffected in both cell types.
The associative long-term potentiation (LTP), which was impaired in CDM animals, was restored by psilocybin. Psilocybin enhances AMPA currents selectively in pyramidal cells, spares interneurons and NMDA receptors, and coincides with restored LTP in a depression model, pointing to a potential mechanism for plasticity-driven antidepressant effects and informing the search for non-hallucinogenic neuroplastogens.