ArticleMolecular and cellular neurosciences2018
Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome.
Article in Molecular and cellular neurosciences, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 41 citations in OpenAlex.
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- Impaired Aggrephagy, Interrupted Vesicular Trafficking, and Cellular Stress, Lead to Protein Aggregation, and Synaptic Dysfunction in Cerebellum of Children and Adults with Idiopathic Autism.Cerebellum (London, England) · 2025Article
- Disease-linked mutations in Munc18-1 deplete synaptic Doc2.Brain : a journal of neurology · 2024Article
- GABAergic/Glycinergic and Glutamatergic Neurons Mediate Distinct Neurodevelopmental Phenotypes ofThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability.Cell reports. Medicine · 2023Article
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- Selective Ablation ofThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.Molecular psychiatry · 2022Article
- Base-edited cynomolgus monkeys mimic core symptoms of STXBP1 encephalopathy.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
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- Recent advances in gene therapy for neurodevelopmental disorders with epilepsy.Journal of neurochemistry · 2021Review
- STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies.Journal of neurochemistry · 2021Review
- Role of Munc18-1 in the biological functions and pathogenesis of neurological disorders (Review).Molecular medicine reports · 2021Review
- Targeted stabilization of Munc18-1 function via pharmacological chaperones.EMBO molecular medicine · 2021Article
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- Age-Related Cognitive Impairment: Role of Reduced Synaptobrevin-2 Levels in Deficits of Memory and Synaptic Plasticity.The journals of gerontology. Series A, Biological sciences and medical sciences · 2020Article
- Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans.Epilepsia · 2020Article
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3 authors at 1 institution in 1 country.
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Abstract
Ohtahara syndrome, also known as type 4 of Early Infantile Epileptic Encephalopathy with suppression bursts (EIEE-4) is currently an untreatable disorder that presents with seizures and impaired cognition. EIEE-4 patients have mutations most frequently in the STXBP1 gene encoding a Sec protein, munc18-1. The exact molecular mechanism of how these munc18-1 mutations cause impaired cognition, remains elusive. The leading haploinsufficiency hypothesis posits that mutations in munc18-1 render the protein unstable leading to its degradation. Expression driven by the healthy allele is not sufficient to maintain the physiological function resulting in haploinsufficiency. The aim of this study has been to understand how munc18-1 haploinsufficiency causes cognitive impairment seen in EIEE-4. Here we present results from behavioral to cellular effects from a mouse model of munc18-1 haploinsufficiency. Munc18-1 heterozygous knock-out mice showed impaired spatial learning and memory in behavior tests as well as reduced synaptic plasticity in hippocampal CA1 long-term potentiation. Cultured munc18-1 heterozygous hippocampal neurons had significantly slower rate of synaptic vesicle release and decreased readily releasable vesicle pool compared to wild-type control neurons in fluorescent FM dye assays. These results demonstrate that reduced munc18-1 levels are sufficient to impair learning and memory by reducing neurotransmitter release. Therefore, our study implicates munc18-1 haploinsufficiency as a primary cause of cognitive impairment seen in EIEE-4 patients.
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