An astrocytic ensemble at vHip-NAc synapses modulates cognitive impairments induced by chronic tetrahydrocannabinol exposure.

Abstract

Cannabis is the most widely used illicit drug, particularly during adolescence. Its consumption disrupts glutamate homeostasis and synaptic plasticity in the nucleus accumbens (NAc). Here, we identify a functionally distinct accumbal astrocytic ensemble, associated with the ventral hippocampus-NAc (vHip→NAc) circuit, that is critical for tetrahydrocannabinol (THC)-induced synaptic and behavioral impairments. We employed the AstroLight tool to selectively manipulate this astrocytic ensemble. Our findings reveal that THC increases astrocytic calcium activity and glutamatergic tone within the NAc. These glutamatergic alterations are absent in astrocyte-specific p38α knockout mice, implicating p38α signaling in astrocyte-mediated plasticity. Astrocytic glutamate release within the vHip→NAc ensemble is required for THC-induced cognitive deficits, and targeted attenuation of THC-induced calcium activity in this ensemble prevents spatial learning and synaptic plasticity impairments. These results highlight a critical role for astrocytic ensembles in shaping behavior and emphasize their potential as therapeutic targets for mitigating the cognitive consequences of THC exposure.