PROCEEDINGS OF THE 10th SRCA SYMPOSIUM – May 2019 - SHEFFIELD, UK
PROCEEDINGS OF THE 10th SRCA SYMPOSIUM – May 2019 - SHEFFIELD, UK
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第十届 SRCA 研讨会论文集 – 2019 年 5 月 - 英国谢菲尔德
DOI：
10.1007/s12311-019-01049-x
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Konczak J.
中科院分区：
文献类型：
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作者：
Draganova R;Pfaffenrot V;Göricke M;Timmann D;Konczak J.
自闭症谱系障碍（ASD）是一种普遍的神经发育疾病，通常涉及影响突触机制的突变。最近，小脑参与ASD已被提出，但潜在的功能改变仍不清楚。在此，我们利用全细胞膜片钳记录与电压敏感染料成像（VSD i）在WT和IB 2 KO小鼠的急性小脑切片的组合，以研究单神经元和微电路特性。IB 2基因（chr22q13.3末端区域）缺失发生在几乎所有的McDermid综合征病例中，导致自闭症症状和运动技能获得严重延迟。这些小鼠的颗粒层揭示了突触传递、神经元兴奋和长时程突触可塑性的严重改变。在IB 2 KO颗粒细胞中增加2.5倍的NMDA受体介导电流增强突触可塑性（WT = 20.4 ± 4.2%，n=12 vs. IB 2 KO = 107.7 ± 44.4，n=9; p<0.05）沿着兴奋/抑制（E/I）平衡（WT = 0.98 ± 0.27，n=6对比IB 2 KO = 2.78 ± 0.32，n=7; p<0.01）。与此同时，颗粒层对苔藓纤维输入的响应的空间组织从“墨西哥帽”转变为“烟囱帽”轮廓，在核心具有更强的激发（WT = 12.9 ± 1.7 μm vs. IB 2 KO = 29.5 ± 4.9 μm，两者n=5; p<0.01）和周围的有限抑制（WT/KO比IWT/ KO = 2.83 ± 0.17，n=5）。因此，IB 2 KO小鼠模型构成了以NMDA受体功能获得为中心的复杂小脑突触病，在几个方面类似于在皮质微柱中也观察到的改变。小脑输入阶段的信号处理的深刻变化揭示了一个可能的新机制，有助于自闭症样行为的发病机制。
Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASD has been suggested but the underlying functional alterations remained obscure. Herein, we exploited a combination of whole-cell patch-clamp recordings with voltage sensitive dye imaging (VSDi) in acute cerebellar slices in WT and IB2 KO mice to investigate single-neuron and microcircuit properties. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan–McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition. The granular layer of these mice revealed severe alterations in synaptic transmission, neuronal excitation and long-term synaptic plasticity. A 2.5-times larger NMDA receptormediated current in IB2 KO granule cells enhanced synaptic plasticity (WT = 20.4 ± 4.2 %, n=12 vs. IB2 KO = 107.7 ± 44.4, n=9; p<0.05) along with the excitatory/inhibitory (E/I) balance (WT = 0.98 ± 0.27, n=6 vs. IB2 KO = 2.78 ± 0.32, n=7; p<0.01). At the same time, the spatial organization of granular layer responses to mossy fiber inputs shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core (WT = 12.9 ± 1.7 μm vs. IB2 KO = 29.5 ± 4.9 μm, n=5 for both; p<0.01) and limited inhibition in the surround (WT/KO ratio IWT/ KO = 2.83 ± 0.17, n=5). The IB2 KO mouse model therefore configures a complex cerebellar synaptopathy centered on NMDA receptor gain of function, that in several respects resembles alterations also observed in cortical minicolumns. The profound changes of signal processing at the cerebellar input stage unveil a possible new mechanism contributing to the pathogenesis of autistic-like behavior.