Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Neurosci Bull. 2022 Jun;38(6):591-606. doi: 10.1007/s12264-022-00824-x. Epub 2022 Feb 11.
Abnormal synchronous neuronal activity has been widely detected by brain imaging of autistic patients, but its underlying neural mechanism remains unclear. Compared with wild-type mice, our in vivo two-photon imaging showed that transgenic (Tg1) mice over-expressing human autism risk gene MeCP2 exhibited higher neuronal synchrony in the young but lower synchrony in the adult stage. Whole-cell recording of neuronal pairs in brain slices revealed that higher neuronal synchrony in young postnatal Tg1 mice was attributed mainly to more prevalent giant slow inward currents (SICs). Both in vivo and slice imaging further demonstrated more dynamic activity and higher synchrony in astrocytes from young Tg1 mice. Blocking astrocytic gap junctions markedly decreased the generation of SICs and overall cell synchrony in the Tg1 brain. Furthermore, the expression level of Cx43 protein and the coupling efficiency of astrocyte gap junctions remained unchanged in Tg1 mice. Thus, astrocytic gap junctions facilitate but do not act as a direct trigger for the abnormal neuronal synchrony in young Tg1 mice, revealing the potential role of the astrocyte network in the pathogenesis of MeCP2 duplication syndrome.
异常同步的神经元活动已在自闭症患者的脑成像中被广泛检测到，但其潜在的神经机制仍不清楚。与野生型小鼠相比，我们的活体双光子成像显示，过度表达人类自闭症风险基因 MeCP2 的转基因 (Tg1) 小鼠在幼年期表现出更高的神经元同步性，但在成年期则较低。脑片神经元对记录显示，年轻 Tg1 小鼠中更高的神经元同步性主要归因于更普遍的巨大慢内向电流 (SICs)。体内和切片成像进一步证明，年轻 Tg1 小鼠的星形胶质细胞具有更活跃的活动和更高的同步性。阻断星形胶质细胞缝隙连接显著减少了 Tg1 大脑中 SICs 的产生和整体细胞同步性。此外，Tg1 小鼠中 Cx43 蛋白的表达水平和星形胶质细胞缝隙连接的偶联效率保持不变。因此，星形胶质细胞缝隙连接促进但不作为年轻 Tg1 小鼠异常神经元同步的直接触发因素，揭示了星形胶质细胞网络在 MeCP2 重复综合征发病机制中的潜在作用。
