Behavioral and electrophysiological outcomes of tissue-specific Smn knockdown in Drosophila melanogaster.
Behavioral and electrophysiological outcomes of tissue-specific Smn knockdown in Drosophila melanogaster.
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DOI：
10.1016/j.brainres.2012.10.035
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发表时间：
2012-12-13
期刊：
影响因子：
2.9
通讯作者：
Sanyal S
中科院分区：
文献类型：
--
作者：
Timmerman C;Sanyal S
人类运动神经元生存蛋白1（SMN1）的严重减少会导致脊髓性肌萎缩症（SMA），这是一种使人衰弱的儿童疾病，可导致神经肌肉系统的进行性损伤。尽管先前的研究试图确定SMN1丢失最严重导致疾病的组织，但这种广泛表达的蛋白质的组织特异性功能仍不清楚。在这里，我们利用RNA干扰的方法来操纵SMN功能选择性地在果蝇神经元或肌肉，其次是行为和电生理分析。运动表现的高分辨率测量显示运动模式的深刻变化后，泛神经元敲除SMN。此外，运动表型可以通过运动神经元中的SMN敲低引起，支持先前在小鼠中运动神经元特异性SMN功能的证明。电生理学上，肌肉中的SMN调制揭示了幼虫神经肌肉接头处的基本上正常的突触传递、量子释放和跨突触稳态补偿。神经元SMN敲低不改变基线突触传递、突触耗竭的动力学或急性稳态补偿。然而，神经肌肉接头处的慢性谷氨酸受体依赖性发育稳态在神经元SMN减少后强烈减弱。总之，这些结果支持SMN功能的分布式模型，其具有不同的神经元特异性作用，这些作用可能在患者的SMN整体丧失后受到损害。虽然补充，并在广泛的协议，最近的小鼠研究表明，强烈的必要性，SMN在神经元，我们的研究结果揭示了迄今未得到充分重视的作用，SMN在运动突触的稳态调节机制。
Severe reduction in Survival Motor Neuron 1 (SMN1) protein in humans causes Spinal Muscular Atrophy (SMA), a debilitating childhood disease that leads to progressive impairment of the neuro-muscular system. Although previous studies have attempted to identify the tissue(s) in which SMN1 loss most critically leads to disease, tissue-specific functions for this widely expressed protein still remain unclear. Here, we have leveraged RNA interference methods to manipulate SMN function selectively in Drosophila neurons or muscles followed by behavioral and electrophysiological analysis. High resolution measurement of motor performance shows profound alterations in locomotor patterns following pan-neuronal knockdown of SMN. Further, locomotor phenotypes can be elicited by SMN knockdown in motor neurons, supporting previous demonstrations of motor neuron-specific SMN function in mice. Electrophysiologically, SMN modulation in muscles reveals largely normal synaptic transmission, quantal release and trans-synaptic homeostatic compensation at the larval neuro-muscular junction. Neuronal SMN knockdown does not alter baseline synaptic transmission, the dynamics of synaptic depletion or acute homeostatic compensation. However, chronic glutamate receptor-dependent developmental homeostasis at the neuro-muscular junction is strongly attenuated following reduction of SMN in neurons. Together, these results support a distributed model of SMN function with distinct neuron-specific roles that are likely to be compromised following global loss of SMN in patients. While complementary to, and in broad agreement with, recent mouse studies that suggest a strong necessity for SMN in neurons, our results uncover a hitherto under-appreciated role for SMN in homeostatic regulatory mechanisms at motor synapses.
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DOI：
10.1097/nen.0b013e31821cbd8b
发表时间：
2011-06-01
影响因子：
3.2
作者：
Dachs, Elisabet;Hereu, Marta;Esquerda, Josep E.
通讯作者：
Esquerda, Josep E.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
1.9
作者：
Balabanian, Sylvia;Gendron, Nathalie H.;MacKenzie, Alex E.
通讯作者：
MacKenzie, Alex E.
影响因子：
64.5
作者：
Dickman, DK;Horne, JA;Schwarz, TL
通讯作者：
Schwarz, TL
影响因子：
3.5
作者：
Burlet, P;Huber, C;Lefebvre, S
通讯作者：
Lefebvre, S