Astrocytic TCF7L2 Impacts Brain Osmoregulation and Restricts Neuronal Excitability

Astrocytes differentiate and mature during postnatal development, but the molecular mechanisms linking their maturation to neuronal function remain unclear. We investigated the role of Wnt/β‐catenin signaling and its effector, the transcription factor TCF7L2, in postnatal astrocytes using single‐nucleus RNA sequencing, imaging, morphometric analysis, microdialysis, and electrophysiology in Tcf7l2 conditional knockout (cKO) mice. Loss of Tcf7l2 caused widespread transcriptional dysregulation in astrocytes, particularly in genes related to amino acid and ion transport, as well as membrane potential regulation. These mice showed disrupted amino acid homeostasis, astrocyte swelling, and impaired extracellular potassium clearance in the somatosensory cortex. These astrocytic changes were accompanied by altered gene expression in cortical pyramidal neurons, reduced excitability, and a hyperpolarized resting membrane potential. Our results suggest that astrocytic TCF7L2 is crucial in coordinating ion and amino acid transport in adulthood, thereby contributing to maintaining extracellular homeostasis and supporting neuronal function. This study identifies TCF7L2 as a key regulator of astrocyte‐mediated neurophysiological support and underscores the importance of its role in astrocyte maturation during postnatal development.