Synapse elimination in the central nervous system

 描述(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输者，起源于运动皮质的V层，是下行运动通路的主要传出来源。这项建议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，以便不同的大脑区域能够发展特定的功能，并避免刺激过载。我们刚刚开始认识到，不正确的突触消除会导致癫痫、自闭症和精神分裂症等神经疾病1-7。然而，对于突触消除在正常神经回路形成中所起的作用，以及突触消除缺陷如何导致体内神经回路形成和功能的异常，我们的认识还存在很大差距。我们最近建立了独特的动物模型，通过在发育过程中选择性地操纵特定神经群体中的基因来消除突触缺陷。我们的初步数据表明，跨膜信号素Sema6D及其丛A1(PlexA1)受体之间的相互作用调节了活性依赖的皮质脊髓突触消除。我们发现，在出生后早期，CS轴突与脊髓神经元形成一过性突触。然而，在缺乏受体PlexA1的小鼠中，这些突触并不会被消除。重要的是，PlexA1突变体表现出中断的熟练动作。因此，我们假设Sema6D-PlexA1介导的突触消除是熟练运动过程中正确的肌肉活动模式所必需的。第一个目标将确定Sema6D-PlexA1信号是否以活动依赖的方式通过RhoA控制突触消除。第二个目标将研究是否通过Sema6D-PlexA1信号消除皮质脊髓神经元和特定类型的脊髓神经元之间的突触。最后，第三个目的将确定Sema6D-PlexA1介导的CSN突触消除是否是熟练动作的肌肉活动模式所必需的。

 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.