PDF(Pubmed)
Abstract：
An increasing number of pathogenic variants in presynaptic proteins involved in the synaptic vesicle cycle are being discovered in neurodevelopmental disorders. The clinical features of these synaptic vesicle cycle disorders are diverse, but the most prevalent phenotypes include intellectual disability, epilepsy, movement disorders, cerebral visual impairment, and psychiatric symptoms ( Verhage and Sørensen, 2020; Bonnycastle et al., 2021; John et al., 2021; Melland et al., 2021). Among this growing list of synaptic vesicle cycle disorders, the most frequent is STXBP1 encephalopathy caused by de novo heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1; Verhage and Sørensen, 2020; John et al., 2021). STXBP1 is an essential protein for presynaptic neurotransmitter release. Its haploinsufficiency is the main disease mechanism and impairs both excitatory and inhibitory neurotransmitter release. However, the disease pathogenesis and cellular origins of the broad spectrum of neurological phenotypes are poorly understood. Here we generate cell type-specific Stxbp1 haploinsufficient male and female mice and show that Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons causes developmental delay, epilepsy, and motor, cognitive, and psychiatric deficits, recapitulating majority of the phenotypes observed in the constitutive Stxbp1 haploinsufficient mice and STXBP1 encephalopathy. In contrast, Stxbp1 haploinsufficiency in glutamatergic neurons results in a small subset of cognitive and seizure phenotypes distinct from those caused by Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons. Thus, the contrasting roles of excitatory and inhibitory signaling reveal GABAergic/glycinergic dysfunction as a key disease mechanism of STXBP1 encephalopathy and suggest the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.
摘要：
在神经发育障碍中发现了与突触小泡周期有关的突触前蛋白中越来越多的致病变体。这些突触小泡周期障碍的临床特征是多种多样的，但最普遍的表型包括智力残疾，癫痫,运动障碍,大脑视觉障碍，和精神症状(Verhage和Sørensen，2020年；Bonnycastle等人。,2021年；约翰等人。,2021年；梅兰等人。,2021)。在越来越多的突触小泡周期障碍中，最常见的是由syntaxin结合蛋白1（STXBP1，也称为MUNC18-1）的新杂合致病变异引起的STXBP1脑病（Verhage和Sørensen，2020年；约翰等人。,2021)。STXBP1是突触前神经递质释放的必需蛋白。其单倍体功能不足是主要的疾病机制，并损害兴奋性和抑制性神经递质的释放。然而,对广谱神经表型的疾病发病机制和细胞起源了解甚少。在这里，我们产生了细胞类型特异性的Stxbp1单倍体不足的雄性和雌性小鼠，并表明在GABA能/甘氨酸能神经元中Stxbp1单倍体不足会导致发育延迟，癫痫,电机,认知，和精神缺陷，概括了在组成型Stxbp1单倍体不足小鼠和STXBP1脑病中观察到的大多数表型。相比之下,谷氨酸能神经元中的Stxbp1单倍体不足导致一小部分认知和癫痫发作表型，与GABA能/甘氨酸能神经元中的Stxbp1单倍体不足引起的表型不同。因此，兴奋性和抑制性信号的对比作用揭示了GABA能/甘氨酸能功能障碍是STXBP1脑病的关键疾病机制,并提示了通过靶向特定神经递质系统选择性调节疾病表型的可能性.意义陈述STXBP1中的杂合致病变异是小儿癫痫的五大原因，也是神经发育障碍的最常见原因之一。它们影响突触前神经递质的释放和神经发育障碍中常见的广泛的神经系统特征，但是疾病的发病机制和这些表型的细胞类型仍不清楚。在这里，我们报道了GABA能/甘氨酸能和谷氨酸能神经元在STXBP1脑病发病机制中的不同作用。这些结果将通过提示针对不同神经元类型的治疗STXBP1脑病的治疗策略的潜在结果来帮助治疗干预措施的发展。
