ASTROCYTIC MGLUR5 SIGNALING TUNES EMOTIONAL AND COGNITIVE PROCESSING IN THE ADULT BRAIN

Astrocytes have emerged as active modulators of synaptic activity. Astrocytes detect glutamate through the activation of the metabotropic glutamate receptor 5 (mGluR5). However, most existing research has focused on the role of mGluR5 in developing rodents or in pathological contexts, likely because of the reported lower levels of astrocytic mGluR5 expression in adulthood. Importantly, prior studies have demonstrated mGluR5-mediated signaling in astrocytes of adult mice, supporting a role for this receptor. Therefore, the main objectives of this study were to determine whether mGluR5 is sufficient to activate astrocytes in the adult brain and to investigate how this activation regulates circuit function and behavior. For these, we evaluated adult mice using loss- and gain-of-function manipulations to assess synaptic plasticity and behavior. First, we found that astrocytes in adult mice exhibit functional mGluR5-dependent signaling. To assess its role, we induced mGluR5 deletion in astrocytes throughout the mouse brain. This deletion resulted in the development of anxious- and depressive-like behaviors, reduced recognition memory, and increased behavioral flexibility, highlighting the hippocampus as a key region. A viral-driven ablation in this area demonstrated that astrocytic mGluR5 is involved in synaptic plasticity. Behaviorally, the deletion of astrocytic mGluR5 recapitulated anxious-like behaviors and impaired recognition memory. Surprisingly, it improved place recognition memory but reduced behavioral flexibility. Lastly, overexpressing this receptor to enhance mGluR5 signaling specifically in hippocampal astrocytes impaired place recognition memory but improved behavioral flexibility, revealing a role for astrocytic mGluR5 for these behaviors. Overall, astrocytic mGluR5 is biologically relevant in adulthood and modulates hippocampal function.