Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity and enhances fear memory

Astrocytes are active players in brain function. They sense and respond to neuronal activity by elevating intracellular calcium levels. These calcium elevations exhibit complex spatiotemporal patterns across the soma and main processes and focal microdomains. This activity underlies the astrocytic involvement in synaptic transmission, metabolism, and brain homeostasis. Here, we performed a multi-level analysis of the IP3 receptor type 2 knockout (IP3R2 KO) mouse model lacking global calcium elevations in astrocytes to disclose its implications to the molecular, cellular, and behavior levels. Transcriptomic analysis of hippocampal tissue revealed differential expression of numerous genes, including 76 regulated by the astrocyte-specific Foxo1 transcription factor. Morphological analysis of hippocampal pyramidal neurons of this model revealed a shift to a more immature spine profile, which may underlie the previously described reduction of long-term depression and performance in a fear memory task. Indeed, we found that these mice lacking global astrocyte calcium display an enhancement of long-term fear memory. To confirm causality between Foxo1 levels and the observed changes, we used a viral approach to induce the overexpression of Foxo1 in hippocampal astrocytes in C57BL/6J mice. The overexpression of Foxo1 in hippocampal astrocytes replicated the structural, synaptic, and behavioral effects observed in mice lacking global calcium elevations in astrocytes. Altogether, these findings support a relationship between astrocytic calcium-dependent signaling, Foxo1 transcriptional regulation, and their overarching influence on circuit structure and function. This work contributes to the evolving field of astrocyte research and underscores the significance of astrocytes in shaping behavior and memory processes.