Altered Synaptic Transmission and Excitability of Cerebellar Nuclear Neurons in a Mouse Model of Duchenne Muscular Dystrophy.
Altered Synaptic Transmission and Excitability of Cerebellar Nuclear Neurons in a Mouse Model of Duchenne Muscular Dystrophy.
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DOI：
10.3389/fncel.2022.926518
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发表时间：
2022
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
杜氏肌营养不良症（DMD）通常被认为是一种肌肉消耗性疾病。然而，DMD的人类患者和动物模型也经常显示非进行性认知缺陷和与神经发育障碍的高共病性，表明中枢处理受损。先前的研究已经确定小脑回路，特别是浦肯野细胞中的异常抑制传递，作为中枢神经系统（CNS）功能障碍的潜在部位。在这项工作中，我们调查潜在的功能障碍，小脑的输出，下游浦肯野细胞（PC）的活动。我们研究了幼年野生型和mdx小鼠（一种常见的DMD小鼠模型）小脑神经核（小脑回路的主要输出）兴奋性投射神经元的突触传递和放电行为。使用免疫标记和电生理学，我们发现PC突触接触的数量减少，但突触后GABAA受体表达或聚集在这些细胞中没有变化。此外，我们发现，浦肯野末梢的突触囊泡的补充率在mdx神经元中降低，这表明这些突触的功能障碍可能主要是突触前的。我们还发现了小脑核神经元兴奋性的变化。具体来说，我们发现更大的自发放电，但减少诱发放电从一个超极化的基线mdx神经元。动作电位波形分析显示，mdx神经元的诱发动作电位复极更快，后超极化更大，表明电压门控或钙门控钾电流增加。我们没有发现野生型核神经元中肌营养不良蛋白或信使RNA（mRNA）表达的证据，这表明在这些细胞中观察到的变化可能是由于突触前PC中肌营养不良蛋白的丢失。总之，这些数据表明，肌营养不良蛋白的丢失降低了小脑核神经元中突触传递和放电的动态范围，可能会破坏小脑回路到其他大脑区域的输出，并导致与DMD相关的认知和神经发育缺陷。
Duchenne muscular dystrophy (DMD) is generally regarded as a muscle-wasting disease. However, human patients and animal models of DMD also frequently display non-progressive cognitive deficits and high comorbidity with neurodevelopmental disorders, suggesting impaired central processing. Previous studies have identified the cerebellar circuit, and aberrant inhibitory transmission in Purkinje cells, in particular, as a potential site of dysfunction in the central nervous system (CNS). In this work, we investigate potential dysfunction in the output of the cerebellum, downstream of Purkinje cell (PC) activity. We examined synaptic transmission and firing behavior of excitatory projection neurons of the cerebellar nuclei, the primary output of the cerebellar circuit, in juvenile wild-type and mdx mice, a common mouse model of DMD. Using immunolabeling and electrophysiology, we found a reduced number of PC synaptic contacts, but no change in postsynaptic GABAA receptor expression or clustering in these cells. Furthermore, we found that the replenishment rate of synaptic vesicles in Purkinje terminals is reduced in mdx neurons, suggesting that dysfunction at these synapses may be primarily presynaptic. We also found changes in the excitability of cerebellar nuclear neurons. Specifically, we found greater spontaneous firing but reduced evoked firing from a hyperpolarized baseline in mdx neurons. Analysis of action potential waveforms revealed faster repolarization and greater after-hyperpolarization of evoked action potentials in mdx neurons, suggesting an increased voltage- or calcium- gated potassium current. We did not find evidence of dystrophin protein or messenger RNA (mRNA) expression in wild-type nuclear neurons, suggesting that the changes observed in these cells are likely due to the loss of dystrophin in presynaptic PCs. Together, these data suggest that the loss of dystrophin reduces the dynamic range of synaptic transmission and firing in cerebellar nuclear neurons, potentially disrupting the output of the cerebellar circuit to other brain regions and contributing to cognitive and neurodevelopmental deficits associated with DMD.
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影响因子：
3.7
作者：
Cheron G;Sausbier M;Sausbier U;Neuhuber W;Ruth P;Dan B;Servais L
通讯作者：
Servais L
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1002/pros.22625
发表时间：
2013-06
期刊：
The Prostate
影响因子：
--
作者：
Chen CL;Mahalingam D;Osmulski P;Jadhav RR;Wang CM;Leach RJ;Chang TC;Weitman SD;Kumar AP;Sun L;Gaczynska ME;Thompson IM;Huang TH
通讯作者：
Huang TH
影响因子：
46.9
作者：
Cadwell CR;Palasantza A;Jiang X;Berens P;Deng Q;Yilmaz M;Reimer J;Shen S;Bethge M;Tolias KF;Sandberg R;Tolias AS
通讯作者：
Tolias AS
DOI：
10.1073/pnas.1302310110
发表时间：
2013-10-01
影响因子：
11.1
作者：
Chaumont, Joseph;Guyon, Nicolas;Isope, Philippe
通讯作者：
Isope, Philippe