Viana, J. F.; Dias, J. D.; Gonzalez-Arias, C.; Alves, L. S.; Veiga, A.; Abreu, D. S.; Machado, J. L.; Barsanti, S.; Pereira de Almeida, L.; Nobre, R. J.; Perea, G.; Oliveira, J. F.

The hippocampus is a brain region involved in both emotion regulation and higher cognitive functions. Astrocytes have emerged as active modulators of synaptic activity, capable of sensing, integrating, and responding to neuronal signals. At glutamatergic synapses, 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 astrocytic mGluR5 expression levels in adulthood compared to postnatal stages. Importantly, prior studies and our preliminary data have demonstrated mGluR5-mediated signaling in astrocytes of adult mice, supporting a role for this receptor. Therefore, the main objectives of this study were (1) to determine whether these lower levels of mGluR5 are sufficient to activate astrocytes in the adult brain and (2) to investigate whether this activation is involved in regulating circuit function and behavior. To address these objectives, we evaluated adult mice employing a combination of calcium-imaging in astrocytes, and loss- and gain-of-function manipulations to assess synaptic plasticity and behavior in adult mice. First, we found that astrocytes of adult mice display fully functional mGluR5-dependent calcium activity. To examine the role of this activity, we induced the deletion of mGluR5 in astrocytes across the entire brain of adult mice. These mice developed anxious- and depression-like behaviors, along with reduced sociability and recognition memory, but showed increased behavioral flexibility. These results highlighted the hippocampus as a key region for mGluR5-mediated astrocytic influence on behavior, leading us to specifically target hippocampal astrocytes. A viral-driven ablation in this area demonstrated that astrocytic mGluR5 plays a role in both basal transmission and the regulation of synaptic plasticity. Behaviorally, the deletion of astrocytic mGluR5 in the hippocampus recapitulated anxious-like behaviors, social deficits, and impaired long-term 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 in regulating these behaviors. Overall, our results confirmed the biological relevance of astrocytic mGluR5 during adulthood, specifically in modulating hippocampal function.