PDF(Pubmed)
Abstract：
Although hyperactivity is associated with a wide variety of neurodevelopmental disorders, the early embryonic origins of locomotion have hindered investigation of pathogenesis of these debilitating behaviors. The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons (MNs) that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Gap junction electrical synapses drive early spontaneous behavior in zebrafish, prior to the emergence of chemical neurotransmitter networks. We use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show altered sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 34/35. We further show that this hyperexcitable behavior can be rescued by pharmacological inhibition of electrical synapses. We also use functional imaging to examine MN and interneuron (IN) activity in early embryogenesis, finding genetic disruption of electrical gap junctions uncouples activity between mnx1 + MNs and INs. Taken together, our work highlights the importance of electrical synapses in motor development and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initial formation of locomotive circuits.
摘要：
尽管多动症与各种各样的神经发育障碍有关，运动的早期胚胎起源阻碍了对这些衰弱行为发病机理的研究。脊椎动物中最早的运动输出是由占据脊髓不同区域的早期出生的运动神经元簇产生的。神经支配刻板的肌肉群。缝隙连接电突触驱动斑马鱼的早期自发行为，在化学神经递质网络出现之前。我们使用多动症的遗传模型来深入了解电机电路形成和功能错误的后果，发现脆性X综合征（FXS）模型突变斑马鱼从自发行为的最早阶段就可以过度兴奋，显示对电间隙连接阻塞的敏感性改变，并增加了间隙连接蛋白连接蛋白34/35的表达。我们进一步表明，这种过度兴奋的行为可以通过药理学抑制电突触来挽救。我们还使用功能成像来检查早期胚胎发生中的运动神经元和中间神经元活动，发现电缝隙连接的遗传破坏使mnx1运动神经元和中间神经元之间的活动解耦。一起来看,我们的工作强调了电突触在运动发育中的重要性，并表明神经发育障碍多动症的起源可能是在机车电路的初始形成过程中建立的。重要性陈述神经发育障碍多动症的起源在脊椎动物系统中很难确定。斑马鱼机车电路在早期胚胎发生中启动，定义的运动神经元和中间神经元驱动最早的机车运动。使用多动症的遗传模型，我们表明，脆性X综合征模型fmr1突变胚胎表现出过度兴奋的行为，并在运动电路神经元上表达过量的间隙连接连接蛋白。我们进一步表明，这种过度兴奋的行为可以通过药理学抑制电突触来挽救。一起来看,这些数据表明过度活跃的行为始于神经发育的最早阶段。
