ASTROCYTIC FOXO1 REGULATES HIPPOCAMPAL SPINOGENESIS AND SYNAPTIC PLASTICITY, ENHANCING 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, main processes, and focal microdomains. This activity underlies the astrocytic involvement in synaptic transmission, metabolism, and brain homeostasis. Here, we performed a multilevel analysis of the IP₃ receptor type 2 knockout (IP₃R2KO) mouse model, which lacks global calcium elevations in astrocytes, to elucidate its implications at the molecular, cellular, and behavioral 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 in this model revealed a shift toward a more immature spine profile, which may underlie the previously described reduction in long-term depression and performance in a fear memory task. Indeed, we found that these mice lacking global astrocytic calcium display enhanced long-term fear memory.
To confirm causality between Foxo1 levels and the observed changes, we used a viral approach to overexpress Foxo1 in hippocampal astrocytes in C57BL/6J mice. This manipulation reproduced the structural, synaptic, and behavioral effects observed in mice lacking global astrocytic calcium elevations. Conversely, silencing Foxo1 in hippocampal astrocytes of IP₃R2KO mice reversed the enhanced fear memory, indicating that elevated Foxo1 mediates this effect. Additionally, calcium imaging provided exploratory insight into astrocytic activity under Foxo1 manipulation.
Altogether, these findings support a relationship between astrocytic calcium-dependent signaling, Foxo1 transcriptional regulation, and their overarching influence on circuit structure and function.