CHRONIC GLUTAMATERGIC MODULATION RESTORES CORTICAL CIRCUIT FUNCTION AND AMELIORATES SEIZURE, MOTOR, AND BEHAVIORAL PHENOTYPES IN STXBP1 ENCEPHALOPATHY

STXBP1 encephalopathy is a prevalent neurodevelopmental disorder characterized by early-onset epilepsy, intellectual disability, motor impairment, and severe behavioral abnormalities. Converging evidence indicates that these symptoms arise from disrupted excitation–inhibition balance caused by impaired excitatory synaptic transmission and deficient recruitment of cortical parvalbumin-positive basket cells. Despite its severity, effective disease-modifying therapies remain unavailable.
Here, we tested whether chronic positive allosteric modulation of glutamatergic signaling can restore circuit function in a mouse model of STXBP1 encephalopathy. Using brain slice electrophysiology, we show that treatment with an AMPA receptor positive allosteric modulator (CX516) or the NMDA receptor co-agonist precursor L-serine normalizes basket cell morphology and partially restores their functional recruitment within cortical feedforward inhibitory circuits, leading to rebalanced excitability of pyramidal neurons. Importantly, chronic in vivo treatment with L-serine resulted in a robust reduction of spontaneous seizures and produced significant improvements across multiple behavioral domains, including decreased aggressive behavior, reduced tremor and hypotonia, and improved locomotor performance.
Together, these findings identify impaired glutamatergic drive as a central mechanism underlying network, motor, and behavioral dysfunction in STXBP1 encephalopathy. They further demonstrate that sustained enhancement of glutamatergic signaling—particularly via L-serine—can restore circuit stability and ameliorate a broad spectrum of disease-relevant phenotypes, supporting its potential as a mechanism-based therapeutic strategy for early intervention.