An astrocytic ensemble at vHip-NAc synapses modulates cognitive impairments induced by chronic tetrahydrocannabinol exposure.
Cristina Martín-Monteagudo, Javier Sánchez Romero, Julia Adams, Nagore Puente, Pedro Grandes, Giovanni Marsicano, Ana Covelo, Baljit S Khakh, Marta Navarrete
Nature Communications December 9, 2025 DOI: 10.1038/s41467-025-67166-w (opens in new tab) via PubMed
Summary
AI-generated from the abstractCannabis, the most widely used illicit drug, is often consumed during adolescence. Its active component, THC, disrupts glutamate balance and synaptic plasticity in the nucleus accumbens (NAc). A specific group of astrocytes in the NAc, linked to the ventral hippocampus-NAc circuit, is critical for these effects. Using the AstroLight tool, researchers found that THC increases calcium activity and glutamate release in these astrocytes. This glutamate release depends on p38α signaling, as mice lacking astrocytic p38α showed no such changes. Blocking THC-induced calcium activity in this astrocyte ensemble prevented spatial learning and synaptic plasticity impairments, highlighting these astrocytes as potential therapeutic targets.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Key finding | THC-induced cognitive deficits require astrocytic glutamate release within a specific ventral hippocampus-NAc ensemble, and attenuating calcium activity in these astrocytes prevents spatial learning and synaptic plasticity impairments. |
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.