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RESTORING CORTICAL CIRCUIT FUNCTION IN STXBP1 ENCEPHALOPATHY WITH L-SERINE AND AN AMPA RECEPTOR MODULATOR
Joakim Palmqvistand 16 co-authors
University of Copenhagen
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-342
Presentation
Date TBA
Board: PS05-09AM-342
Event Information
Poster Board
PS05-09AM-342
Poster
View posterAbstract
Syntaxin-binding protein 1 (STXBP1) is critical for both excitatory and inhibitory neurotransmission. Mutations in STXBP1 cause a severe neurodevelopmental disorder characterized by frequent seizures, for which existing treatments, which focus on seizure management, have limited efficacy. STXBP1 encephalopathy arises because impaired excitatory synapses fail to recruit inhibitory interneurons, disrupting the balance between excitation and inhibition throughout the neocortex. We therefore hypothesized that positive allosteric modulators (PAMs) of glutamate receptors might paradoxically limit hyperexcitability. Indeed, the AMPA receptor PAM CX1739 and the NMDA receptor co-agonist D-serine mitigated cortical hyperexcitability in brain slices from a Stxbp1 haploinsufficient mouse model by enhancing recruitment of interneurons. In naturally behaving mice, both CX1739 and the D-serine precursor L-serine augmented interneuron recruitment and reduced spike-wave discharges. These findings reveal that CX1739 and L-serine are a promising mechanism-based therapy for STXBP1 encephalopathy that could be readily translated to clinical trials.
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