Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability

De novo mutations in Stxbp1 are among the most prevalent causes of neurodevelopmental disorders, and lead to haploinsufficiency, cortical hyperexcitability, epilepsy and other symptoms. Given that Munc18-1, the protein encoded by Stxbp1, is essential for both excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We discovered that overall inhibition in canonical feedforward microcircuits is defective in a validated mouse model for Stxbp1 haploinsufficiency. However, unexpectedly, we found that inhibitory synapses were largely unaffected. Instead, excitatory synapses failed to recruit inhibitory interneurons. Modelling experiments confirmed that defects in the recruitment of inhibitory neurons in microcircuits cause hyperexcitation. Ampakines, compounds that enhance excitatory synapses, restored interneuron recruitment and prevented hyperexcitability. These findings identify deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy design. Highlights- Neocortical microcircuits fail in Stxbp1 haploinsufficiency mouse models (Stxbp1hap) - Microcircuit impairments leads to cortical hyperexcitability due to a lack of inhibition. - Inhibitory synapses are not severely affected in Stxbp1hap, instead, excitatory synapses fail to recruit interneurons. - AMPAkines rescue microcircuit failure in Stxbp1hap