Astrocytic Chromatin Remodeler ATRX Gates Hippocampal Memory Consolidation through Metabolic and Synaptic Regulation

Astrocytes are increasingly recognized as active regulators of synaptic transmission and memory, yet the epigenetic mechanisms underlying their contribution to cognitive processes remain poorly defined. Here, we investigated the role of the chromatin remodeler ATRX in astrocytes by generating mice with inducible, astrocyte-specific Atrx deletion (aiKO) using tamoxifen administration at postnatal days 10–12, resulting in ATRX loss in approximately half of hippocampal and cortical astrocytes. Transcriptomic profiling of hippocampal tissue at one and three months revealed a progressive increase in differentially expressed genes, with early enrichment for cytoskeletal and immune pathways and later dysregulation of energy metabolism, ion transport, and synaptic gene sets. Electrophysiological recordings from CA1 pyramidal neurons in aiKO slices demonstrated increased neuronal excitability, reduced membrane capacitance, and decreased frequency of spontaneous excitatory postsynaptic currents, indicating non-cell-autonomous neuronal dysfunction. Morphological analysis identified a transient reduction in dendritic branching at one month and a selective loss of thin dendritic spines by three months, without changes in total dendrite length or overall spine density. Behaviorally, aiKO mice displayed normal locomotion, anxiety, and short-term memory, but exhibited deficits in 24-hour novel object recognition and long-term spatial memory in the Morris water maze. These findings demonstrate that ATRX-mediated chromatin remodeling in astrocytes is essential for maintaining hippocampal transcriptional homeostasis, neuronal function, and long-term memory. Our results highlight a critical role for astrocytic epigenetic regulation in cognitive processes and suggest that astrocyte dysfunction may contribute to the pathogenesis of ATR-X syndrome and related intellectual disability disorders, underscoring the importance of targeting multiple cell types for therapeutic intervention.