Microcircuit failure inSTXBP1encephalopathy leads to hyperexcitability

Abstract

SummaryDe novomutations inStxbp1are 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 byStxbp1, 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 forStxbp1haploinsufficiency. 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 inStxbp1disorder and identify compounds enhancing excitation as a direction for therapy design.Highlights- Neocortical microcircuits fail inStxbp1haploinsufficiency mouse models (Stxbp1hap)- Microcircuit impairments leads to cortical hyperexcitability due to a lack of inhibition.- Inhibitory synapses are not severely affected inStxbp1hap, instead, excitatory synapses fail to recruit interneurons.- AMPAkines rescue microcircuit failure inStxbp1hap