Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Psychedelics modulate the serotonergic system, enhancing neuroplasticity.
• Therapeutic effects of psychedelics are linked to cognitive and emotional regulation changes.
• The molecular mechanisms of psychedelic-induced plasticity are not fully understood.

Purpose of the Study:

• To investigate the persistent, cell type-specific molecular changes induced by psychedelics.
• To identify alternative splicing alterations following psychedelic administration.
• To explore the connection between splicing changes and neuronal function.

Main Methods:

• Deep RiboTag sequencing and bioinformatics analysis in mouse medial prefrontal cortex (mPFC).
• Assessment of gene expression and alternative splicing patterns.
• Analysis of extracellular matrix, synaptic, and intrinsic neuronal physiology.

Main Results:

• A single psychedelic dose induced modest gene expression changes but significant, long-lasting alternative splicing shifts.
• Alternative splicing alterations persisted for at least one month post-treatment.
• Splicing changes correlated with alterations in extracellular matrix, synaptic, and parvalbumin interneuron physiology.

Conclusions:

• Psychedelics induce persistent, cell type-specific alternative splicing changes in the mPFC.
• These splicing alterations are a key molecular mechanism underlying psychedelic-induced neuroplasticity.
• The findings provide a valuable resource for understanding psychedelic effects on cortical function.