Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.
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DOI：
10.1038/nn.4561
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发表时间：
2017-07
影响因子：
25
通讯作者：
Mentis GZ
中科院分区：
文献类型：
--
作者：
Fletcher EV;Simon CM;Pagiazitis JG;Chalif JI;Vukojicic A;Drobac E;Wang X;Mentis GZ
神经退行性疾病中的行为缺陷通常归因于脆弱神经元通过细胞自主机制的选择性功能障碍。虽然脆弱的神经元嵌入在神经元回路中，但它们的突触伙伴对疾病过程的贡献在很大程度上是未知的。在这里，我们表明，在脊髓性肌萎缩症（SMA）的小鼠模型中，本体感受性突触驱动的减少导致运动神经元功能障碍和运动行为障碍。在SMA小鼠中或在本体感受性突触传递阻断后，我们观察到运动神经元放电减少，这可以通过运动神经元表面钾通道Kv2.1表达减少来解释。通过体内慢性暴露增加神经元活性导致Kv2.1表达正常化和运动功能改善。我们的研究结果表明，兴奋性突触驱动在发育过程中塑造运动神经元功能的关键作用，以及其破坏对神经退行性疾病的贡献。
Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. Here, we show that in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity pharmacologically by chronic exposure in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.