PDF(Pubmed)
Abstract：
Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+ IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.
摘要：
Dystroglycan（Dag1）是一种跨膜糖蛋白，可将细胞外基质与肌动蛋白细胞骨架连接。Dag1或其糖基化所需的基因的突变会导致营养不良，一种先天性肌营养不良，其特征是广泛的表型，包括肌肉无力，大脑缺陷,和认知障碍。我们研究了中间神经元(IN)的发育，突触功能，以及多种小鼠模型中相关的癫痫发作易感性，这些模型反映了广泛的表型范围。由于Dag1或Pomt2的前脑缺失（这是Dystroglycan糖基化所必需的），显示CCK+/CB1R+IN发展显著受损。CCK+/CB1R+IN轴突未能正确靶向海马锥体神经元的体树突区室，导致突触缺陷和癫痫发作易感性增加。缺乏Dystroglycan胞内结构域的小鼠在CCK+/CB1R+轴突靶向方面有较温和的缺陷，但却表现出抑制性突触功能的戏剧性变化，表明该结构域的关键突触后作用。相比之下,CCK+/CB1R+IN突触功能和癫痫发作易感性在模型小鼠中由于部分减少的肌聚糖糖基化而导致轻度肌营养不良病正常。总的来说，这些数据表明，抑制性突触缺陷和癫痫发作易感性升高是严重营养不良病的标志，并表明Dystroglycan在组织功能性抑制性突触组装中起着重要作用。
