Exploring Neurodevelopmental Encephalopathies through STXBP1: Insights and Therapeutic Approaches

titleExploring Neurodevelopmental Encephalopathies through STXBP1: Insights and Therapeutic Approaches
start_date2024/12/16
schedule11h
onlineno
location_infosalle de conférence Albe-Fessard
summaryMutations in the STXBP1 gene are a major contributor to neurodevelopmental disorders, leading to haploinsufficiency, which is associated with cortical hyperexcitability, epilepsy, and various other symptoms. The STXBP1 gene encodes the protein Munc18-1, crucial for both excitatory and inhibitory synaptic signaling. However, the mechanisms by which these mutations result in cortical hyperexcitability are not well understood. In our study, we identify defects in the inhibitory control of neural circuits in a mouse model with STXBP1 haploinsufficiency. Surprisingly, inhibitory synapses formed by parvalbumin-positive (PV) interneurons remain largely unaffected. Instead, we observe that excitatory neurons fail to effectively recruit these inhibitory interneurons, disrupting the balance of excitation and inhibition (E/I balance) in the cortex. We then test whether positive allosteric modulators (PAMs) targeting glutamate receptors can restore this balance. In brain slices, we demonstrate that PAMs for AMPA and NMDA receptors successfully prevent cortical hyperexcitability by promoting the recruitment of PV interneurons, thus re-establishing E/I balance. Further in vivo experiments show that these compounds such also restore basket cell recruitment, resulting in a marked reduction in spike-wave discharges, a model for absence seizures observed in humans. These findings reveal a potential therapeutic strategy by targeting specific microcircuit deficiencies, which could be expedited to clinical trials given that certain glutamate receptor PAMs are already regulated as dietary supplements. This approach represents a promising pathway for developing treatments for STXBP1-related neurodevelopmental disorders.
responsiblesPerignon

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submittedpublished2024/12/12 15:12 UTC
speakers
Perrier
Event #2414899 - latest update on 2024/12/12, created on 2024/12/12