Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis
Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis
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DOI：
10.1093/cercor/bhu317
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发表时间：
2016-04-01
期刊：
影响因子：
3.7
通讯作者：
Zona, C.
中科院分区：
文献类型：
--
作者：
Saba, L.;Viscomi, M. T.;Zona, C.
肌萎缩侧索硬化症（ALS）是一种致命性疾病，其特征是脑脊髓轴运动神经元逐渐退化。作为 ALS 的一个特征，上运动神经元过度兴奋是否会通过顺行过程引发谷氨酸代谢功能障碍和下运动神经元退化，目前尚不清楚。为了检查上运动神经元活动的早期变化是否与谷氨酸能改变相关，我们进行了全细胞膜片钳记录，以分析家族性 ALS (fALS) 模型的症状前 G93A 小鼠中 V 层皮质运动神经元的兴奋特性和兴奋性突触后电流 (EPSC)。我们发现 G93A V 层锥体神经元表现出改变的 EPSC 频率和流变碱值，表明其过度兴奋状态。这些过度兴奋的神经元的生物胞素负载揭示了它们的基底树突树枝化的扩张。此外，我们检测到 G93A 小鼠皮质 V 层中囊泡谷氨酸转运蛋白 2 的表达水平增加。总而言之，我们的数据表明，功能和结构神经元的改变与症状前 G93A 小鼠运动皮层的异常谷氨酸能活性相关。这些异常预计会增强谷氨酸的释放并有利于其在运动皮层中的积累，为上运动神经元参与 ALS 发病机制早期的观点提供了强有力的支持。
Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of motor neurons in the cerebrospinal axis. Whether upper motor neuron hyperexcitability, which is a feature of ALS, provokes dysfunction of glutamate metabolism and degeneration of lower motor neurons via an anterograde process is undetermined. To examine whether early changes in upper motor neuron activity occur in association with glutamatergic alterations, we performed whole-cell patch-clamp recordings to analyze excitatory properties of Layer V cortical motor neurons and excitatory postsynaptic currents (EPSCs) in presymptomatic G93A mice modeling familial ALS (fALS). We found that G93A Layer V pyramidal neurons exhibited altered EPSC frequency and rheobase values indicative of their hyperexcitability status. Biocytin loading of these hyperexcitable neurons revealed an expansion of their basal dendrite arborization. Moreover, we detected increased expression levels of the vesicular glutamate transporter 2 in cortical Layer V of G93A mice. Altogether our data show that functional and structural neuronal alterations associate with abnormal glutamatergic activity in motor cortex of presymptomatic G93A mice. These abnormalities, expected to enhance glutamate release and to favor its accumulation in the motor cortex, provide strong support for the view that upper motor neurons are involved early on in the pathogenesis of ALS.