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

中枢神经系统（CNS）由神经元和神经胶质细胞组成。NG 2-神经胶质细胞是成人大脑中的主要增殖细胞，它们占所有细胞的约5%。它们也被称为少突胶质细胞祖细胞（OPCs），正如它们的名字所暗示的那样，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CNS髓磷脂，其对于快速和能量有效的神经传导以及对于信号的正确定时和同步是必需的。活动依赖性髓鞘形成允许CNS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需的。虽然大多数髓鞘在生命早期形成，但越来越多的证据表明髓鞘形成持续到成年后期，并且一些NG 2-胶质细胞需要在成人大脑中不断分化成新的少突胶质细胞以维持髓鞘结构和运动能力。然而，它还没有完全理解如何NG 2-神经胶质细胞分化在成人中枢神经系统的调节。此外，NG 2-神经胶质细胞在整个CNS中的高数量和均匀分布，也在从未成为髓鞘的区域中，表明NG 2-神经胶质细胞除了作为祖细胞的作用之外还有其他目的，但这种功能可能是什么仍然不清楚。有趣的是，NG 2-神经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，只发生在无髓鞘轴突节段，可能是NG 2-胶质细胞分化的调节器。然而，关于神经元-NG 2-胶质细胞突触功能的数据是相当矛盾的，根据实验设计，研究人员发现NG 2-胶质细胞突触可能影响增殖，分化，细胞存活或迁移。因此，我的目标是在拟议中的项目是研究NG 2神经胶质突触在成人中枢神经系统中使用一种新的和更有针对性的方法的功能。为了特异性地破坏神经元-神经胶质细胞突触通讯，我们已经产生了一种新的小鼠模型，其具有可诱导的少突胶质细胞谱系特异性条件性缺失的Shank 3基因，Shank 3是突触后密度的中央支架蛋白。人类SHANK 3的缺失破坏了兴奋性神经元突触，并导致了自闭症谱系障碍（ASD）的Escheran-McDermid综合征。在我们的小鼠中诱导转基因导致特别是在少突胶质细胞谱系细胞中的Shank 3的主要同种型的缺失，以破坏NG 2-神经胶质突触，但留下完整的神经元突触。我将研究这种细胞特异性Shank 3缺失对NG 2-胶质细胞增殖、分化和髓鞘以及神经元-NG 2-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。该项目的结果不仅有助于回答NG 2-胶质细胞在成人CNS中的功能的重要生理问题，而且还可能揭示NG 2-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.