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<p>The STXBP1 protein critically regulates synaptic vesicle fusion and neurotransmitter release, with its mutations implicated in neurodevelopmental disorders. <i>STXBP1</i> R406H can lead to the occurrence of early-onset epileptic encephalopathy (EOEE). To better elucidate the molecular mechanisms underlying pathogenesis，we generated an <i>STXBP1</i> R406H mutation mouse model that recapitulated key cognitive-social deficits observed in patients. Behavioral and transcriptomic analyses revealed synaptic impairments and glial activation in mutant mice. Specifically, there is abnormal expression of synaptic proteins in hippocampal neurons, which are correlated with cognitive and motor deficits. Our study establishes that the <i>STXBP1</i> R406H mutation drives neurodevelopmental pathology via excitatory synaptic dysfunction, offering new mechanistic insights and therapeutic avenues for the treatment of STXBP1-related disorders.</p>

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Cognitive and Motor Dysfunction in STXBP1 R406H Mice

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • Hua Liu,
  • Ya-ze Duan,
  • Shang Li,
  • Yi Hu,
  • Xiao Mao,
  • Yong Cheng

摘要

The STXBP1 protein critically regulates synaptic vesicle fusion and neurotransmitter release, with its mutations implicated in neurodevelopmental disorders. STXBP1 R406H can lead to the occurrence of early-onset epileptic encephalopathy (EOEE). To better elucidate the molecular mechanisms underlying pathogenesis，we generated an STXBP1 R406H mutation mouse model that recapitulated key cognitive-social deficits observed in patients. Behavioral and transcriptomic analyses revealed synaptic impairments and glial activation in mutant mice. Specifically, there is abnormal expression of synaptic proteins in hippocampal neurons, which are correlated with cognitive and motor deficits. Our study establishes that the STXBP1 R406H mutation drives neurodevelopmental pathology via excitatory synaptic dysfunction, offering new mechanistic insights and therapeutic avenues for the treatment of STXBP1-related disorders.