Duchenne muscular dystrophy (DMD) patients, having mutations of the DMD gene, present with a range of neuropsychiatric disorders, in addition to the quintessential muscle pathology. The neurobiological basis remains poorly understood because the contributions of different DMD gene products (dystrophins) to the different neural networks underlying such symptoms are yet to be fully characterised. While full-length dystrophin clusters in inhibitory synapses, with inhibitory neurotransmitter receptors, the precise subcellular expression of truncated DMD gene products with excitatory synapses remains unresolved. Furthermore, inflammation, involving P2X purinoceptor 7 (P2RX7) accompanies DMD muscle pathology, yet any association with brain dystrophins is yet to be established. The aim of this study was to investigate the comparative expression of different dystrophins, alongside ionotropic glutamate receptors and P2RX7s, within the cerebellar circuitry known to express different dystrophin isoforms. Immunoreactivity for truncated DMD gene products was targeted to Purkinje cell (PC) distal dendrites adjacent to, or overlapping with, signal for GluA1, GluA4, GluN2A, and GluD2 receptor subunits. P2X7R immunoreactivity was located in Bergmann glia profiles adjacent to PC-dystrophin immunoreactivity. Ablation of all DMD gene products coincided with decreased mRNA expression for Gria2, Gria3, and Grin2a and increased GluD2 immunoreactivity. Finally, dystrophin-null mice showed decreased brain mRNA expression of P2rx7 and several inflammatory mediators. The data suggest that PCs target different dystrophin isoforms to molecularly and functionally distinct populations of synapses. In contrast to muscle, dystrophinopathy in brain leads to the dampening of the local immune system.

中文翻译：

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特定的抗肌营养不良蛋白选择性地与小鼠小脑的抑制性和兴奋性突触相关，其丢失会改变 P2X7 嘌呤受体和促炎症介质的表达。


杜氏肌营养不良症 (DMD) 患者存在 DMD 基因突变，除了典型的肌肉病理学之外，还会出现一系列神经精神疾病。神经生物学基础仍然知之甚少，因为不同的 DMD 基因产物（肌营养不良蛋白）对这些症状背后的不同神经网络的贡献尚未得到充分表征。虽然全长肌营养不良蛋白与抑制性神经递质受体聚集在抑制性突触中，但截短的 DMD 基因产物与兴奋性突触的精确亚细胞表达仍未解决。此外，涉及 P2X 嘌呤受体 7 (P2RX7) 的炎症伴随着 DMD 肌肉病理学，但与脑肌营养不良蛋白的任何关联尚未确定。本研究的目的是调查已知表达不同肌营养不良蛋白亚型的小脑回路中不同肌营养不良蛋白以及离子型谷氨酸受体和 P2RX7 的比较表达。截短的 DMD 基因产物的免疫反应性靶向与 GluA1、GluA4、GluN2A 和 GluD2 受体亚基信号相邻或重叠的浦肯野细胞 (PC) 远端树突。 P2X7R 免疫反应性位于与 PC 肌营养不良蛋白免疫反应性相邻的伯格曼神经胶质细胞分布中。所有 DMD 基因产物的消融与 Gria2、Gria3 和 Grin2a mRNA 表达减少以及 GluD2 免疫反应性增加同时发生。最后，肌营养不良蛋白缺失小鼠的大脑中 P2rx7 和几种炎症介质的 mRNA 表达降低。数据表明，PC 将不同的肌营养不良蛋白亚型靶向分子和功能上不同的突触群体。与肌肉相反，大脑中的肌营养不良症会导致局部免疫系统受到抑制。