Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability

Cell Rep Med. 2023 Dec 19;4(12):101308. doi: 10.1016/j.xcrm.2023.101308. Epub 2023 Dec 11.

Abstract

De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy.

Keywords: cortex; epilepsy; feedforward inhibition; microcircuits; neurodevelopmental encephalopathy; synaptic transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Diseases* / genetics
  • Brain Diseases* / metabolism
  • Humans
  • Mice
  • Munc18 Proteins / genetics
  • Munc18 Proteins / metabolism
  • Mutation
  • Neurons / metabolism
  • Synapses / metabolism
  • Synaptic Transmission / genetics

Substances

  • Munc18 Proteins
  • STXBP1 protein, human
  • Stxbp1 protein, mouse