Increased Plasticity in Hippocampus and Prefrontal Cortex Following Psychedelic Administration

INSIGHT 2023 Replay from the Basic Research Track:

Talk – Synaptic Plasticity, Metaplasticity, and the Neurophysiological Effects of Psychedelics
Zarmeen Zahid, MSc
PhD Candidate, University of Wisconsin–Madison

Serotonergic psychedelics have shown remarkable clinical efficacy in treating conditions such as major depressive disorder and anxiety. However, the precise neurophysiological mechanisms behind their long-lasting therapeutic benefits remain unclear. In this data-rich talk, Zarmeen Zahid explores whether psychedelics induce synaptic plasticity and metaplasticity in brain regions critical to mood regulation—specifically the hippocampus and medial prefrontal cortex (mPFC).

Using ex vivo and in vivo electrophysiology in mice, Zahid investigates changes in synaptic excitability and plasticity following administration of psychedelics including DOI, psilocybin, 4-AcO-DMT, and 6-FDET, compared to ketamine and saline controls. Recordings were taken at multiple time points from both the hippocampal Schaffer collateral pathway and the vHPC–mPFC circuit, a pathway often disrupted in psychiatric and stress-related conditions.

Findings revealed acute increases in synaptic excitability across limbic regions and evidence of metaplasticity in the hippocampus—suggesting that these shifts in neural dynamics may play a role in the therapeutic effects seen in humans. However, metaplasticity was not observed in the mPFC, highlighting the complexity of region-specific responses to psychedelic administration.

This research provides key mechanistic insights into how psychedelics may modulate brain circuits underlying emotion and cognition, and underscores the need for continued investigation into how these changes translate into lasting therapeutic outcomes.

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