The role of synaptic communication between neurons and NG2-glia in the adult brain

成人大脑中神经元和 NG2 神经胶质细胞之间突触通讯的作用

• 批准号: 444583389
• 负责人: Dr. Katrin Volbracht, Ph.D.
• 金额: --
• 依托单位: Universitätsklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/444583389?language=en
• 关键词: role; synaptic; communication; between; neurons

The central nervous system (CNS) consists of neurons and glial cells. NG2-glia are the main proliferating cells in the adult brain where they comprise around 5% of all cells. They are also known as oligodendrocyte progenitor cells (OPCs) and are, as their name implies, able to generate new oligodendrocytes throughout life. Oligodendrocytes form the CNS myelin that is essential for fast and energy efficient nerve conduction and for the correct timing and synchronisation of signals. Activity dependent myelination allows for CNS plasticity as the generation of new oligodendrocytes has been shown to be required for motor learning. Although most of the myelin is formed early in life, there is growing evidence that myelination continues into late adulthood and that some NG2-glia need to continuously differentiate into new oligodendrocytes in the adult brain to maintain the myelin structure and motor abilities. However, it is not yet fully understood how NG2-glia differentiation in the adult CNS is regulated. Moreover, the high number and even distribution of NG2-glia throughout the CNS, also in areas that never become myelinated, suggest that NG2-glia serve some other purpose in addition to their role as progenitors, but what that function could be is still unclear.Interestingly, NG2-glia also form synapses with neuronal axons and act as post-synapse for neuronal inputs. These synapses, which only occur on unmyelinated axonal segments, may be regulators of NG2-glia differentiation. However, the data regarding the function of neuron-NG2-glia synapses are rather contradictory, and depending on the experimental design, researchers found that NG2-glia synapses may affect proliferation, differentiation, cell survival or migration. My aim in the proposed project is thus to study the function of NG2-glia synapses in the adult CNS using a novel and more targeted approach. To specifically disrupt the neuron-glia synaptic communication we have generated a new mouse model with an inducible oligodendrocyte lineage specific conditional deletion in the gene for Shank3, a central scaffold protein at the postsynaptic density. The deletion of SHANK3 in humans disrupts excitatory neuronal synapses and causes the Phelan-McDermid syndrome, an autism spectrum disorder (ASD). Induction of the transgene in our mice leads to the deletion of the major isoforms of Shank3 specifically in oligodendrocyte lineage cells to disrupt NG2-glia synapses but leave neuronal synapses intact. I will study the effect of this cell specific Shank3 deletion on NG2-glia proliferation, differentiation and on myelin as well as on the morphology and function of the neuron-NG2-glia synapses themselves. Moreover, I will assess how these cellular changes affect the motor, cognitive and social abilities of the mice. The results of this project will not only help to answer the important physiological question of the function of NG2-glia in the adult CNS but may also uncover a role for NG2-glia in ASD.

中枢神经系统(CNS)由神经元和胶质细胞组成。NG2-胶质细胞是成人大脑中主要的增殖细胞，约占所有细胞的5%。它们也被称为少突胶质前体细胞(OPC)，顾名思义，它们能够在一生中产生新的少突胶质细胞。少突胶质细胞形成中枢神经系统髓鞘，对于快速和能量高效的神经传导以及信号的正确计时和同步是必不可少的。由于新的少突胶质细胞的产生被证明是运动学习所必需的，因此依赖活动的髓鞘形成允许中枢神经系统的可塑性。尽管大多数髓鞘是在生命早期形成的，但越来越多的证据表明，髓鞘形成持续到成年后期，一些NG2胶质细胞需要在成人大脑中不断分化为新的少突胶质细胞，以维持髓鞘结构和运动能力。然而，目前还不完全清楚NG2-神经胶质细胞在成年中枢神经系统中的分化是如何调节的。此外，NG2-胶质细胞在整个中枢神经系统中的数量和均匀分布也表明，NG2-胶质细胞除了作为祖细胞发挥作用外，还具有其他用途，但其功能仍不清楚。有趣的是，NG2-胶质细胞还与神经元轴突形成突触，并作为神经元输入的突触后。这些突触只出现在无髓鞘轴突节段，可能是NG2-胶质细胞分化的调节因素。然而，关于神经元-NG2-神经胶质突触功能的数据相当矛盾，研究人员发现，根据实验设计，NG2-神经胶质突触可能会影响增殖、分化、细胞存活或迁移。因此，我在拟议的项目中的目的是使用一种新的、更有针对性的方法来研究成年中枢神经系统中NG2-胶质细胞突触的功能。为了具体干扰神经元-神经胶质突触的通讯，我们建立了一个新的小鼠模型，在突触后密度的中心支架蛋白Shank3的基因中，具有可诱导的少突胶质细胞谱系特异性的条件性缺失。人类中SHANK3基因的缺失扰乱了兴奋性神经元突触，并导致了费兰-麦克德米德综合征，这是一种自闭症谱系障碍(ASD)。在我们的小鼠中诱导转基因导致Shank3主要亚型的缺失，特别是在少突胶质细胞谱系细胞中，以破坏NG2-神经胶质突触，但保持神经元突触完整。我将研究这种细胞特异性的Shank3缺失对NG2-胶质细胞的增殖、分化和髓鞘的影响，以及对神经元-NG2-胶质细胞突触本身的形态和功能的影响。此外，我将评估这些细胞变化如何影响小鼠的运动、认知和社交能力。本项目的结果不仅有助于回答NG2-胶质细胞在成人中枢神经系统中的功能这一重要生理学问题，而且还可能揭示NG2-胶质细胞在ASD中的作用。