Mapping excitatory synaptic plasticity evoked by single-dose psilocybin in mice

A single dose of psilocybin can trigger enduring antidepressant effects in mice, but the underlying neurobiological mechanisms remain unclear, especially concerning synaptic function and drug-target specificity. Researchers aimed to uncover the single-dose psilocybin-induced excitatory synaptic plasticity. They assessed synaptic plasticity using whole-cell patch-clamp recording of excitatory synaptic transmission 24 hours post-treatment with a single dose of psilocybin.

The recordings were correlated with transcriptomic data and validated using a conditional single-vector CRISPR/SaCas9-dependent knockout strategy to establish the role of the 5-HT2A receptor. Psilocybin selectively enhanced the frequency of miniature excitatory postsynaptic currents within specific cortical sub-regions and the amygdala.

This frequency correlated with the expression levels of psilocin-targeted serotonin receptors, accounting for expression heterogeneity across cortical regions and along the anterior-posterior axis. Deleting the post-synaptic Htr2a gene in the insular/orbitofrontal cortex abolished psilocybin-induced 24-hour plasticity. These findings reveal that lasting psilocybin-induced modifications to excitatory synaptic transmission occur with brain-region specificity, likely reflecting the functional impact of synapse formation.

This study lays the groundwork for a circuit-specific, mechanistic comprehension of the functional dimensions of psilocybin-induced neuroplasticity.