Glutamine synthetase sustains cortical circuit development via mTOR-mediated astrocyte maturation

Glutamine synthetase (GS), a key metabolic enzyme converting glutamate to glutamine, is essential for maintaining neurotransmitter balance and nitrogen homeostasis. While its loss in adults leads to neurodegeneration, its role in early cortical development has remained unclear. Here, we show that cortex-specific GS deletion in mice disrupts postnatal cortical circuit maturation by impairing astrocyte development. GS-deficient astrocytes exhibit reduced morphological complexity and molecular immaturity, despite preserved cell numbers. Single-nucleus transcriptomics and metabolic profiling reveal suppressed mTOR signaling and broad amino acid imbalances in mutant astrocytes. These deficits compromise astrocyte-mediated support of synaptogenesis and neuronal function, resulting in dendritic simplification, impaired synaptic transmission, and autism-like behaviors. Our findings identify GS as a critical regulator of astrocyte maturation and highlight the GS–mTOR axis as a metabolic checkpoint in cortical circuit assembly.