The role of metabotropic glutamate and GABA-B receptors in oligodendrocyte development survival and vulnerability in the immature brain

少突胶质细胞位于大脑中被称为白质的区域，在那里它们为神经细胞提供支持。神经细胞通过称为轴突的纤维与其他神经细胞进行交流。通过大脑中的轴突进行快速而可靠的通信，从根本上取决于覆盖轴突的髓鞘。少突胶质细胞是发育过程中产生髓鞘和鞘轴突的特殊脑细胞。少突胶质细胞的正常发育和髓鞘的形成是一个复杂的过程，受到广泛的细胞相互作用的调节。少突胶质细胞对发育中的大脑中的各种化学信号做出反应，并改变它们的增殖、迁移、分化和髓鞘形成。未成熟的少突胶质细胞在发育中的大脑中非常脆弱，如果它们的氧气供应不足(例如：肺功能不佳或出生并发症)，它们往往会受到损害。少突胶质细胞的选择性死亡会严重扰乱新生儿的髓鞘形成，这可能会导致日后的主要神经并发症。记忆和运动障碍通常发生在脑白质中未成熟的少突胶质细胞的广泛损害之后。我们对少突胶质细胞发育的基本机制、它们增加的脆弱性以及促进它们在未成熟大脑中再生的因素的基本了解非常有限。最近，我们发现了一些蛋白质(受体)，它们在未成熟的少突胶质细胞中介导大脑主要递质化学物质谷氨酸和GABA的作用。谷氨酸和GABA是从活跃的神经细胞中释放出来的，它们代表着大脑中包括少突胶质细胞在内的细胞的化学信号。神经细胞中谷氨酸和GABA的活性依赖性释放可能影响脑内少突胶质细胞的发育和存活。本项目的目的是明确这些受体在少突胶质细胞发育、髓鞘形成、白质损伤后的存活和再生中的作用。更好地了解早产儿大脑中的这些基本细胞和分子事件对于制定有效的脑白质损伤治疗策略至关重要。医学进步显著提高了严重早产儿的存活率，70%的早产儿出现了明显的少突胶质细胞损伤。此外，少突胶质细胞损伤是一系列其他神经系统疾病(如多发性硬化症、中风和脊髓损伤)的显著特征。因此，更好地了解损伤后少突胶质细胞发育、存活和再生的基本过程具有重大的公共卫生意义。

Oligodendroglial cells are located in the area of the brain called 'white matter' where they provide support to nerve cells. Nerve cells communicate with other nerve cells via fibres called axons. Fast and reliable communication through axons in the brain fundamentally depends on myelin that covers the axons. Oligodendrocytes are the specialised brain cells that produce this myelin and ensheath axons during development. Normal development of oligodendrocytes and myelin formation are complex procedures, regulated by a wide range of cellular interactions. Oligodendrocytes respond to various chemical signals in the developing brain and they alter their proliferation, migration, differentiation and myelin formation. Immature oligodendroglial cells are very vulnerable in the developing brain and they are often damaged if they are poorly supplied with oxygen (e.g.: poor lung function or birth complications). The selective death of oligodendroglial cells can severely disrupt myelination in newborn infants, which can lead to major neurological complications later in life. Memory and movement disorders frequently develop following extensive lesions of the immature oligodendroglial cells in brain white matter. Our basic understanding of the fundamental mechanisms of oligodendrocyte development, their increased vulnerability and factors that enhance their regeneration in the immature brain is very limited. Recently we have identified proteins (receptors), which mediate the actions of the major brain transmitter chemicals glutamate and GABA in immature oligodendroglial cells. Glutamate and GABA are released from active nerve cells and they represent chemical signals for cells in the brain including the oligodendrocytes. The activity dependent release of glutamate and GABA from nerve cells may influence oligodendrocyte development and survival in the brain. The purpose of this project is to define the role of these receptors in oligodendroglial development, myelin formation, survival and regeneration following white matter damage. Better understanding of these basic cellular and molecular events in the premature brain is essential for the development of effective treatment strategies for white matter damage. Medical advances significantly improved the survival rate of seriously premature infants and 70% of these infants develop prominent oligodendrocyte damage. Furthermore, oligodendrocyte damage is a prominent feature of a range of other neurological diseases (e.g. multiple sclerosis, stroke and spinal cord injury). Therefore better understanding of basic processes of oligodendrocyte development, survival and regeneration following damage has major public health implications.