Astrocytic Foxo1 regulates hippocampal spinogenesis and synaptic plasticity to enhance fear memory

Astrocytes are active players in brain circuits, sensing and responding to neuronal activity, impacting behavior production. Activation of astrocytes triggers intracellular calcium elevations displaying complex spatiotemporal properties. Intracellular calcium activity is thought to underlie synaptic transmission, metabolism, and brain homeostasis modulation. However, the calcium-dependent signaling pathways involved in these processes are poorly understood, representing a critical knowledge gap in this field. To reveal calcium-dependent signaling pathways involved in circuit structure and function, we performed a multi-level analysis of the inositol 1,4,5-triphosphate receptor type 2 knockout (IP3R2 KO) mouse model which lacks somatic calcium elevations specifically in astrocytes. We focused on the hippocampus, a brain region responsible for cognitive function and emotional behaviors. The transcriptomic analysis of hippocampal tissue revealed that the lack of astrocytic somatic calcium causes the differential expression of hundreds of genes. Among these, 76 genes are regulated by the astrocyte-specific Foxo1 transcription factor. This transcription factor is over-expressed in the hippocampal astrocytes of this mouse model and regulates the expression of genes involved in spinogenesis and synaptic coverage. A detailed morphological analysis of hippocampal pyramidal neurons revealed dendrites with a shift to a more immature spine profile. This spine profile shift may underlie previously described a reduction of long-term depression and performance in fear memory tasks observed in this mouse model. Indeed, we confirmed that these mice lacking astrocytic somatic calcium display an enhancement of long-term fear memory. To verify a causal relationship between these structural, synaptic, and behavioral observations, we used a viral approach to induce the over-expression of Foxo1 in hippocampal astrocytes in naive C57BL/6J mice. This viral-driven over-expression of Foxo1 in astrocytes of the stratum radiatum replicated the shift to an immature spine profile in dendrites of pyramidal neurons crossing the territory of these astrocytes and led to a reduction of long-term depression in the same region. Finally, this manipulation was sufficient to enhance long-term fear memory. The detailed characterization of the mouse model lacking astrocytic somatic calcium revealed that astrocytes modulate hippocampal circuit structure and function through Foxo1 signaling to enhance fear memory.