Reelin Deficiency and Synaptic Impairment in the Adolescent Prefrontal Cortex Following Initial Synthetic Cannabinoid Exposure

Abstract

Background

Adolescent cannabinoid exposure can have long-lasting effects on the brain, particularly in the prefrontal cortex, where the reelin protein plays a crucial role in neural organization. Chronic cannabinoid exposure leads to reelin deficiency and behavioral abnormalities, but the underlying mechanisms remain unclear. With the increasing use of synthetic cannabinoids (SCs) among young people, understanding these effects is crucial.

Methods

We examined the cellular and synaptic consequences of initial SC exposure in adolescent male mice 1 day after a single in vivo exposure to WIN 55,212-2. Our approach combined immunohistochemistry, Western blots, conditional CB₁ receptor (CB1R) knockout mouse lines, quantitative polymerase chain reaction, and ex vivo electrophysiology to investigate the effects of SC on reelin expression and synaptic plasticity. Additionally, single-molecule fluorescent in situ hybridization profiling was used to identify cellular coexpression patterns of reelin and CB1Rs.

Results

Our findings indicate that a single exposure to SC decreased reelin expression in specific prefrontal cortex layers accompanied by disrupted proteolytic fragmentation but not changes in messenger RNA expression. Single-molecule fluorescent in situ hybridization profiling revealed a strong coexpression of CB1R and reelin. Furthermore, our pharmacological and genetic approaches demonstrated that CB1Rs in GABAergic (gamma-aminobutyric acidergic) neurons mediate the SC-induced decrease in reelin. This decrease in reelin results in a reduction in long-term potentiation, phenocopying reelin haploinsufficient mice. Notably, we restored long-term potentiation by infusing reelin bilaterally, establishing a functional link between reelin depletion and synaptic deficits.

Conclusions

These findings provide new insights into the neural consequences of adolescent cannabinoid consumption and highlight the critical role of reelin in the cellular mechanisms associated with SC initiation during adolescence.