Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.
Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
J Neurosci. 2013 Apr 24;33(17):7308-7324. doi: 10.1523/JNEUROSCI.0224-13.2013.
Cholinergic overactivity in diseases of neuromuscular transmission elicits a retrograde signal resembling homeostatic synaptic plasticity that downregulates transmitter release. Understanding this compensatory pathway could provide insights into novel therapeutic avenues and molecular mechanisms underlying learning and memory. Here we identify nitric oxide as a possible source of this signal in pathological human and mouse muscle samples and link this signaling pathway to changes in synaptic function in the neuromuscular junction. We further show that neuronal nitric oxide synthase is regulated by cholinergic excess through activation of skeletal muscle calpain and its effect on Cdk5 and CaMKII, leading to direct modulation of presynaptic function. Finally, we show that this signaling pathway acts through specific miRNA control of presynaptic vesicle protein expression. The control of presynaptic miRNA levels by postsynaptic activity represents a novel mechanism for the modulation of synaptic activity in normal or pathological conditions.
神经肌肉传递疾病中的胆碱能过度活跃会引发类似于自身稳定突触可塑性的逆行信号，从而下调递质释放。了解这种代偿途径可以为学习和记忆的新治疗途径和分子机制提供深入了解。在这里，我们确定一氧化氮（NO）是病理性人和小鼠肌肉样本中这种信号的可能来源，并将这种信号通路与神经肌肉接头突触功能的变化联系起来。我们进一步表明，神经元型一氧化氮合酶（nNOS）通过激活骨骼肌钙蛋白酶及其对 Cdk5 和 CaMKII 的作用而受到胆碱能过度的调节，从而直接调节突触前功能。最后，我们表明，这种信号通路通过突触前囊泡蛋白表达的特定 miRNA 控制起作用。突触后活动对突触前 miRNA 水平的控制代表了在正常或病理条件下调节突触活动的新机制。
