Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic exposure
bioRxiv – January 16, 2025
Source: medRxiv/bioRxiv/arXiv
Summary
A single dose of psychedelics can lead to lasting changes in how neurons in the brain communicate. This study reveals that these substances significantly alter gene splicing in key neuron types, enhancing neuroplasticity. These changes may explain improved cognitive and emotional functions following psychedelic use, highlighting their therapeutic potential.
Abstract
Psychedelics engage the serotonergic system as potent neuromodulators, increasing neuroplasticity in humans and rodents. Persistent changes in cognitive flexibility, emotional regulation, and social cognition are thought to underlie the therapeutic effects of psychedelics. However, the underlying molecular and cellular basis of psychedelic-induced plasticity remains unclear. Here, we identify persistent, cell type-specific alternative splicing changes in the mouse medial prefrontal cortex (mPFC) induced by a single dose of psychedelics. Combining deep RiboTag sequencing and bioinformatics, we find that a single dose of psychedelics modestly alters gene expression while dramatically shifting patterns of alternative splicing lasting at least a month. We connect our functional enrichment and alternative splicing analysis with changes in the extracellular matrix, synaptic physiology, and intrinsic physiology in parvalbumin interneurons days to a week after psychedelic treatment. Our dataset is an essential resource for understanding the persistent, cell type-specific effects of psychedelics on cortical cell types and functions.