A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency.
A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency.
复制标题
DOI：
10.1016/j.celrep.2016.06.087
复制
发表时间：
2016-08-02
期刊：
影响因子：
8.8
通讯作者：
Mentis GZ
中科院分区：
文献类型：
--
作者：
Simon CM;Janas AM;Lotti F;Tapia JC;Pellizzoni L;Mentis GZ
脊髓性肌萎缩是一种由运动神经元存活蛋白（SMN）普遍缺乏引起的神经退行性疾病，在运动神经元（MN）丧失之前感觉运动突触功能障碍和兴奋性增加。中枢突触功能障碍和MN过度兴奋是否是细胞自主事件或它们导致MN死亡尚不清楚。我们解决了这些问题，使用基于干细胞的模型的运动电路组成的MN和兴奋性和抑制性中间神经元（IN），其中SMN蛋白水平被选择性耗尽。我们发现，SMN缺陷通过细胞自主机制诱导选择性MN死亡，而超兴奋性是MN对前运动神经元缺陷的非细胞自主反应，导致神经元突触丢失和兴奋减少。从我们的体外模型的结果表明，功能障碍和损失的MN的结果从不同的神经元的运动回路中的SMN缺乏的差异性影响和过度兴奋不会触发MN死亡。
In spinal muscular atrophy—a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein—sensory-motor synaptic dysfunction and increased excitability precede motor neuron (MN) loss. Whether central synaptic dysfunction and MN hyperexcitability are cell autonomous events or they contribute to MN death is unknown. We addressed these issues using a stem cell-based model of the motor circuit consisting of MNs and both excitatory and inhibitory interneurons (INs) in which SMN protein levels are selectively depleted. We show that SMN deficiency induces selective MN death through cell autonomous mechanisms, while hyperexcitability is a non-cell autonomous response of MNs to defects in pre-motor INs leading to loss of glutamatergic synapses and reduced excitation. Findings from our in vitro model suggest that dysfunction and loss of MNs result from differential effects of SMN deficiency in distinct neurons of the motor circuit and that hyperexcitability does not trigger MN death.