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Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability
Altair Brito Dos Santos1, Silas Dalum Larsen1, Liangchen Guo1
1Department of Neuroscience, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
Cell Reports. Medicine
|December 12, 2023
Summary
Mutations in STXBP1 disrupt brain circuits, causing hyperexcitability. Enhancing excitatory synapses with CX516 restored inhibition and prevented seizures in a mouse model, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- STXBP1 mutations are a leading cause of neurodevelopmental disorders, resulting in haploinsufficiency.
- The Munc18-1 protein (encoded by STXBP1) is crucial for synaptic transmission, yet the mechanism behind mutation-induced hyperexcitability remains unclear.
Purpose of the Study:
- To investigate the underlying mechanisms of cortical hyperexcitability in a mouse model of STXBP1 haploinsufficiency.
- To identify potential therapeutic targets for STXBP1-related disorders.
Main Methods:
- Utilized a mouse model (P15-22) exhibiting Stxbp1 haploinsufficiency.
- Examined synaptic function in canonical feedforward microcircuits.
- Employed computational modeling to understand circuit dynamics.
- Tested the efficacy of CX516, an ampakine, in restoring circuit function.
Main Results:
- Overall inhibition in feedforward microcircuits was found to be defective.
- Inhibitory synapses from parvalbumin-positive interneurons were unaffected.
- Excitatory synapses failed to adequately recruit inhibitory interneurons, leading to hyperexcitation.
- CX516 treatment restored interneuron recruitment and ameliorated hyperexcitability.
Conclusions:
- Deficits in excitatory synapses within microcircuits are a key mechanism driving cortical hyperexcitability in Stxbp1 disorder.
- Enhancing excitatory synaptic function represents a promising therapeutic avenue for STXBP1-related neurodevelopmental disorders.
