PSYCHEDELIC-INDUCED REMODELING OF PERINEURONAL NETS AND PARVALBUMIN NEURONS ACROSS THE MOUSE BRAIN

Psychedelic compounds are emerging as promising therapeutics for neuropsychiatric disorders, yet their effects on brain-wide inhibitory circuits remain poorly understood. Perineuronal nets (PNNs) are extracellular matrix structures that primarily enwrap parvalbumin-positive (PV+) interneurons and have been implicated in synaptic plasticity regulation.
Here, we present a comprehensive whole-brain analysis of changes in PNN and PV following single-dose administration of MDMA, psilocybin, or LSD in adult mice. Brains were collected 24 hours post-injection, with an additional MDMA group collected at 48 hours. Using immunohistochemistry for PV and PNN (WFA) combined with automated image analysis, we quantified cell density and staining intensity across approximately 600 brain regions, excluding the cerebellum. We have visualized the findings in an interactive viewer across several anatomical hierarchies, from layer specific to broader areas.
All three compounds displayed divergent effects across different brain areas. A common theme among all treatments was the abundance of areas with reduced PV and PNN density. Intriguingly, in LSD and psilocybin groups, remaining PV+ cells tended to show higher PV intensity levels. An unexpected effect was the large PNN intensity increases for the MDMA treatments. The MDMA groups showed a distinct temporal profile, with stronger effects at 48 hours than at 24 hours. Somatosensory areas were particularly affected in the MDMA groups, while LSD and psilocybin showed larger effects particularly in visual areas and hypothalamus.
These findings provide the first whole-brain characterization of psychedelic effects on PNN and PV+ interneuron populations, offering new insights into mechanisms of psychedelic-induced plasticity.