PSILOCYBIN AFFECTS SYNAPTIC PLASTICITY BY MODULATING MICROGLIAL ACTIVITY

Depression affects ~5.7% of adults worldwide, and up to half of patients do not respond to current treatments. It is associated with reduced hippocampal volume, decreased synapse number—particularly reduced inhibitory synaptic tone—and impaired brain plasticity. Psilocybin has been shown to increase the number of synapses, but it remains unclear whether this effect is mediated solely by neurons or involves other brain cell types as well.It is established now, that brain resident macrophages microglia not only phagocyte pathogens but also eliminate inactive synapses and remodel the extracellular matrix (ECM), thereby influencing synaptic plasticity. Stress increases microglial phagocytic activity, that might lead to excessive synaptic pruning in depression. Conversely, microglial phagocytosis of ECM components may allow new synapse formation.
This study aimed to evaluate the density of inhibitory synapse in a mouse model of depression under psilocybin treatment, and to identify the role of microglia by assessing their phagocytic activity toward inhibitory synapses and ECM. Hippocampi from control, stressed, and psilocybin treated mice were analyzed using immunostaining and fluorescence microscopy. Inhibitory synapses were quantified using VGAT and gephyrin, microglia were labelled by Iba1 and CD68, and ECM was stained using aggrecan and Wisteria floribunda agglutinin.
We found that psilocybin induced a significant increase in ECM uptake by microglia without altering lysosomal volume or number. These findings suggest that modulation of microglial activity and ECM remodeling may underlie the sustained plasticity-promoting effects of psilocybin.