TY - JOUR

T1 - Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability

AU - dos Santos, Altair Brito

AU - Larsen, Silas Dalum

AU - Guo, Liangchen

AU - Barbagallo, Paola

AU - Montalant, Alexia

AU - Verhage, Matthijs

AU - Sørensen, Jakob Balslev

AU - Perrier, Jean François

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - cortex

KW - epilepsy

KW - feedforward inhibition

KW - microcircuits

KW - neurodevelopmental encephalopathy

KW - synaptic transmission

U2 - 10.1016/j.xcrm.2023.101308

DO - 10.1016/j.xcrm.2023.101308

M3 - Journal article

C2 - 38086378

AN - SCOPUS:85180081549

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

SN - 2666-3791

IS - 12

M1 - 101308

ER -