THC DISRUPTS MEMORY CONSOLIDATION VIA GLUTAMATERGIC DYSREGULATION IN THE HIPPOCAMPAL CA1 REGION

The hippocampus plays a pivotal role in memory formation, and cannabinoids, including Δ⁹-tetrahydrocannabinol (THC), are known to modulate hippocampus-dependent memory, alter synaptic and structural plasticity, and disrupt the excitatory/inhibitory (E/I) balance. In particular, the CA1 region has been identified as a critical locus for these effects, where repeated THC exposure has been associated with impaired long-term potentiation and reduced dendritic spine density. Here, we sought to identify cell type–specific molecular mechanisms underlying these alterations following chronic THC exposure, with the goal of developing pharmacological strategies that preserve the therapeutic potential of THC while preventing memory impairment. To decipher the THC-induced translatome, we used Wfs1-CreERT2:RiboTag mice expressing HA-tagged ribosomes selectively in CA1 pyramidal neurons. Mice received daily intraperitoneal injections of THC (10 mg/kg) or vehicle for six days, after which HA-associated mRNAs were isolated and analyzed by RNA sequencing. Bioinformatic analyses of differentially translated transcripts revealed significant enrichment of Gene Ontology and KEGG categories related to memory, synaptic organization, structural plasticity, and glutamatergic transmission, including altered expression of glutamate receptor subunits in THC-treated mice. Guided by these molecular signatures, we tested whether pharmacological modulation of the glutamatergic system could normalize circuit function and rescue behavior. Rebalancing E/I signaling restored performance in hippocampus-dependent memory tasks after repeated THC exposure, while preserving THC-induced analgesia. Collectively, our data identify CA1 pyramidal neuron–specific pathways dysregulated by chronic THC, link these changes to glutamatergic dysfunction and memory deficits, and provide proof-of-concept that targeting synaptic balance can dissociate therapeutic and adverse cognitive effects of cannabinoids.