Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability
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Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability. / dos Santos, Altair Brito; Larsen, Silas Dalum; Guo, Liangchen; Barbagallo, Paola; Montalant, Alexia; Verhage, Matthijs; Sørensen, Jakob Balslev; Perrier, Jean François.
In: Cell Reports Medicine, Vol. 4, No. 12, 101308, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 377804739