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

中枢神经系统（CNS）由神经元和胶质细胞组成。ng2神经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细胞祖细胞（OPCs），顾名思义，它们能够在整个生命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磷脂，髓磷脂对于快速高效的神经传导和正确的信号定时和同步至关重要。活动依赖性髓鞘形成允许中枢神经系统的可塑性，因为新的少突胶质细胞的产生已被证明是运动学习所必需的。尽管大多数髓磷脂在生命早期形成，但越来越多的证据表明，髓磷脂形成持续到成年晚期，一些ng2 -胶质细胞需要在成年大脑中不断分化为新的少突胶质细胞，以维持髓磷脂结构和运动能力。然而，成人中枢神经系统中ng2 -胶质细胞的分化是如何调控的，目前还不完全清楚。此外，ng2 -胶质细胞在整个中枢神经系统中的高数量和均匀分布，也在从未成为髓鞘的区域，表明ng2 -胶质细胞除了作为祖细胞之外还有其他作用，但这种功能可能是什么尚不清楚。有趣的是，ng2 -胶质细胞也与神经元轴突形成突触，并作为神经元输入的突触后。这些突触仅发生在无髓鞘轴突节段，可能是ng2胶质细胞分化的调节因子。然而，关于神经元- ng2 -胶质突触功能的数据相当矛盾，根据实验设计，研究人员发现ng2 -胶质突触可能影响增殖、分化、细胞存活或迁移。因此，我在拟议项目中的目标是使用一种新颖且更具针对性的方法来研究成人中枢神经系统中ng2 -胶质细胞突触的功能。为了特异性地破坏神经元-胶质细胞突触间的通讯，我们建立了一个新的小鼠模型，诱导少突胶质细胞谱系特异性条件缺失Shank3基因，Shank3是突触后密度的中心支架蛋白。人类SHANK3基因的缺失会破坏兴奋性神经元突触，导致费兰-麦克德米综合征，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，破坏ng2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Shank3缺失对ng2 -胶质细胞增殖、分化、髓磷脂以及神经元- ng2 -胶质突触本身形态和功能的影响。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。本项目的研究结果不仅有助于回答ng2 -胶质细胞在成人中枢神经系统中功能的重要生理问题，而且可能揭示ng2 -胶质细胞在ASD中的作用。

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.