Regional roles of astrocytic Foxo1 in the modulation of behavior

Astrocytes are crucial for modulating synaptic activity and behavior through bidirectional communication with neurons. They sense and respond to neuronal activity by elevating intracellular calcium levels, which display complex spatiotemporal properties. To disclose its implications for behavior, we studied the IP3 receptor type 2 knockout (IP3R2 KO) mouse model that lacks global calcium elevations in astrocytes. We found that mice lacking IP3R2 display enhanced fear memory. Molecular analysis of hippocampal tissues revealed hundreds of up or down-regulated genes, among which 76 of those are modulated by the transcription factor Foxo1. To further validate this relationship, a mouse model overexpressing Foxo1 in astrocytes of the dorsal hippocampus was generated, where an increased fear memory was observed. Given the involvement of other cortico-limbic regions in emotional processing and fear memory, we generated mouse models over-expressing Foxo1 in astrocytes of the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). We observed distinct effects of Foxo1 in astrocytes of the BLA and mPFC across various behavioral paradigms, highlighting regional specificity in Foxo1 functional roles. These results indicate alternative involvement of astrocytic calcium-dependent signaling in the modulation of cortico-limbic circuits and behavior.