Pre- and postsynaptic changes at the axo-glial synapses in white matter during de- and remyelination

脱髓鞘事件发生在某些神经系统疾病，如多发性硬化症(MS)时，成熟的少突胶质细胞就会丢失。如果少突胶质前体细胞(OPC)存在于脱髓鞘区域或迁移到脱髓鞘区域，并分化为髓鞘少突胶质细胞，则有时会发生重新髓鞘形成并防止轴突退化。不同的分子和不同类型的细胞相互作用在OPC-轴突识别和再髓鞘形成中发挥作用，但在这方面研究最少的因素之一是轴突的电活动。然而，轴突的电特性很可能参与了重新髓鞘形成的过程，因为它是从发育的髓鞘作用中得知的，神经元在与OPC的接触部位释放神经递质，OPC表达AMPA受体来检测轴突信号，这些轴突突触随着OPC成熟成为发挥髓鞘作用的少突胶质细胞而丢失。然而，应该记住的是，在病理条件下，如脱髓鞘，轴突重新排列和重新表达不同的钠通道亚单位，以恢复进行动作电位的能力，这反过来可能会影响神经递质向OPC的释放。由于再髓鞘作用与发育髓鞘形成有许多相似之处，我假设脱髓鞘白质区域的轴突和OPC无法完全重建通常发生在发育脱髓鞘过程中的突触信号的正确模式。这会导致异常/不完全/延迟的再髓鞘形成。为了研究这些问题，转基因小鼠的体内脱髓鞘和再髓鞘形成模型将结合原位电生理学、免疫组织化学和激光共聚焦扫描显微镜。一方面，突触前部位的变化将被解决，例如，在重新髓鞘形成过程中轴突释放谷氨酸，以及钠通道表达改变时轴突特性的变化。另一方面，研究突触后OPC和少突胶质细胞电生理特性的变化，特别是AMPA受体表达和AMPA亚单位组成(决定钙通透性)的变化。预期的结果将有助于理解轴突-神经胶质通讯在再髓鞘形成中的作用，这对于开发针对神经退行性疾病的再髓鞘形成和轴突保护的新疗法具有重要意义。此外，在成人中枢神经系统的病理条件下，轴-胶质突触在发育期间和重新髓鞘形成期间的差异也将被描述。

After a demyelinating event, as it occurs during certain neurologic diseases like Muliple Sclerosis (MS), mature oligodendrocytes are lost. Remyelination sometimes occurs and prevents axons from degeneration, if oligodendrocyte precursor cells (OPCs) are present in or migrating to the region of demyelination and differentiate into myelinating oligodendrocytes. Different molecules and different types of cellular interactions are known to play a role in OPC-axon recognition and remyelination, yet one of the least investigated factors with this respect is electrical activity in axons. Nevertheless, electrical properties of axons are likely to be involved in the process of remyelination, since it is known from developmental myelination, that neurons release neurotransmitter at contact-sites with OPCs, that OPCs express AMPA receptors to detect axonal signals and that these axo-glial synapses are lost as OPCs mature into oligodendrocytes exerting myelination. Yet, it should be kept in mind that under pathological conditions such as demyelination, axons re-arrange and re-express different sodium channel subunits in order to restore the ability to conduct action potentials, which may in turn affect the release of neurotransmitter towards OPCs.Since remyelination has many similarities with developmental myelination, I hypothesize that axons and OPCs in the demyelinated white matter region fail to fully re-establish correct patterns of synaptic signaling that usually take place during developmental demyelination. This results in abnormal/incomplete/delayed remyelination. To investigate these questions, in vivo models of de- and remyelination in transgenic mice will be combined with in situ electrophysiology, immunohistochemistry, and confocal laser scanning microscopy. On the one hand, changes at the pre-synaptic site will be addressed, e.g. glutamate release by the axon during remyelination and also the changes in axonal properties upon altered sodium channel expression. On the other hand, changes in the electrophysiological properties of OPCs and oligodendrocytes at the postsynaptic site are addressed, in particular alterations in AMPA receptor expression and AMPA subunit composition (determining calcium-permeability).The expected results will help to understand the role of axo-glial communication during remyelination, which is of great importance for the development of new therapies that aim at remyelination and axon preservation in neurodegenerative diseases. In addition, differences between axo-glial synapses during development and during remyelination under pathological conditions in the adult central nervous system will be described.