Synapse elimination in the central nervous system

 描述（由申请人提供）：皮质脊髓神经元是控制自主运动的运动指令的关键传递者，起源于运动皮质的V层，是下行运动通路的主要传出来源。本提案的总体目标是了解突触消除在建立皮质脊髓运动回路和自主运动控制中的作用。在大脑发育过程中，突触数量过多。然而，大脑必须消除多余的突触，使不同的大脑区域可以发展特定的功能，并避免刺激过载。我们刚刚开始认识到，不适当的突触消除有助于神经系统疾病，如癫痫，自闭症和精神分裂症1 -7。然而，我们对突触消除在正常回路形成中所起的作用以及突触消除缺陷如何导致体内异常神经回路形成和功能的认识存在很大差距。我们最近建立了独特的动物模型，通过选择性地操纵发育过程中特定神经群体中的基因，发现了突触消除缺陷。我们的初步数据暗示调节活动依赖性皮质脊髓突触消除之间的相互作用的跨膜semaphorin Sema 6D和其plexinA 1（PlexA 1）受体。我们发现，在出生后的早期发展，CS轴突短暂形成突触与脊髓神经元。然而，这些突触在缺乏PlexA 1受体的小鼠中并没有被消除。重要的是，PlexA 1突变体表现出中断的熟练运动。因此，我们假设Sema 6D-PlexA 1介导的突触消除需要在熟练的运动过程中的肌肉活动的适当模式。第一个目标将确定Sema 6D-PlexA 1信号传导是否以活性依赖性方式通过RhoA控制突触消除。第二个目标将检查皮质脊髓神经元和特定类别的脊髓神经元之间的突触是否被Sema 6D-PlexA 1信号消除。最后，第三个目标将确定Sema 6D-PlexA 1介导的CSN突触消除是否是熟练运动的肌肉活动的正确模式所必需的。

 DESCRIPTION (provided by applicant): Corticospinal neurons, the key conveyers of motor instructions controlling voluntary movement, originate in layer V of the motor cortex and are the major efferent source of descending motor pathways. The overall goal of this proposal is to understand the role of synapse elimination in establishment of corticospinal motor circuits and voluntary movement control. During brain development there is an overabundance of synapse number. However the brain must eliminate excess synapses so that different brain areas can develop specific functions, and avoid stimuli overload. We are just beginning to recognize that improper synapse elimination contributes to neurological disorders such as epilepsy, autism and schizophrenia1-7. However, there are large gaps in our knowledge of the role played by synapse elimination in normal circuit formation and how deficiencies in synapse elimination cause aberrant neural circuit formation and function in vivo. We have recently established unique animal models harboring synapse elimination defects by selectively manipulating genes in specific neural populations during development. Our Preliminary Data implicate regulation of activity-dependent corticospinal synapse elimination by interaction between the transmembrane semaphorin Sema6D and its plexinA1 (PlexA1) receptor. We found that during early postnatal development, CS axons transiently form synapses with spinal neurons. However, these synapses are not eliminated in mice lacking the receptor PlexA1. Importantly, PlexA1 mutants exhibit disrupted skilled movements. Thus we hypothesize that Sema6D-PlexA1-mediated synapse elimination of required for proper patterns of muscle activity during skilled movements. The first aim will determine whether Sema6D-PlexA1 signaling controls synapse elimination via RhoA in an activity-dependent manner. The second aim will examine whether synapses between corticospinal neurons and specific classes of spinal neurons are eliminated by Sema6D-PlexA1 signaling. Finally the third aim will determine whether the Sema6D-PlexA1-mediated CSN synapse elimination is required for co//rrect patterns of muscle activity for skilled movements.