The psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), alters protein signaling in extracellular vesicles (EVs) in the brain. In cell cultures, THC activated choroid plexus epithelial cells, increasing cannabinoid 1 receptor and c-fos gene expression and releasing RNA-containing EVs. In male and female rats, acute or chronic exposure to aerosolized THC changed the protein composition of brain EVs in cerebrospinal fluid, with effects differing by sex and exposure duration. These results suggest that THC modulates intercellular communication in the brain through EV signaling, offering new insight into how external substances can influence brain signaling.
BDNF and STEP61 have opposing roles in the brain, with BDNF supporting synaptic strengthening and STEP61 opposing it. In schizophrenia and related disorders, their expression is often inversely related. Treating cortical neurons or mice with the NMDAR antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms, increased STEP61 levels and decreased BDNF expression. Reducing STEP61, either by knockdown or with the inhibitor TC-2153, prevented the drop in BDNF. The increase in STEP61 inhibited CREB-dependent BDNF transcription. In mice, genetic or pharmacological inhibition of STEP prevented PCP-induced reductions in BDNF and normalized hyperlocomotion and cognitive deficits. The findings suggest a mechanism linking STEP61 to BDNF regulation, with relevance to cognitive dysfunction in central nervous system disorders.