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

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.

Oligodendrocytes (OLs) are responsible for axon myelination and are the principal cells targeted in preterm brain white matter injury (WMI). The cellular and molecular mechanisms involved in OL development, survival and regeneration following WMI in the immature brain is unclear. It is likely, that the major neurotransmitters glutamate and GABA have significant influences on all of these processes. We recently identified the expression of metabotropic glutamate receptors (mGluRs) and GABAB receptors (GABABRs) in developing OLs in both cultured cells and brain samples. While we have established recently that mGluR5 activation prevents apoptosis in OL progenitor cells (OPC) and GABABR activation stimulates OPC proliferation and migration, the precise role of these receptors in the developing brain is unclear. The aim of this project is to further define the functional role of these receptors in OL development, survival and regeneration following damage caused by hypoxia-ischaemia (HI). We will apply a combination of well-established in vitro and in vivo approaches to investigate: a) the role of mGluRs and GABABRs in OPC proliferation, migration, differentiation and myelination during development, b) OL lineage progression in mGluR5 and GABAB1 deficient mice, c) the effects of mGluRs and GABABRs on OL viability and WMI induced by HI, d) the effects of GABABR stimulation on OPC proliferation and myelin regeneration in normal brain and following HI-induced OL damage and e) determine the role of mGluRs and GABABRs in neurofunctional outcome following HI-induced WMI. This integrated multidisciplinary project will reveal fundamental information on the regulation of oligodendrocyte development and vulnerability. Better understanding of these important cellular processes are likely to contribute to the development of novel therapeutic strategies for WMI, a prominent feature of a range of neurological diseases.