Critical function of Kir4.1 for the life-long generation of oligodendrocytes and myelin

The massive computing power of the brain depends on the insulation of nerve cell connections with myelin sheaths, by cells known as oligodendrocytes. Bundles of these 'myelinated' connections form the white matter that is very prominent in the human cortex. The loss of myelin is a feature of multiple neuropathologies, most notably Multiple Sclerosis and other demyelinating diseases. However, myelin loss is also important in the poor clinical outcomes of cerebral palsy, stroke, and traumatic injury. Importantly, oligodendrocytes are continuously being lost and regenerated from a pool of stem cells in the brain, called oligodendrocyte progenitor cells (OPCs). These regenerative processes are essential for the life-long maintenance of myelin and for repair of myelin following damage. The failure or impairment of repair results in the loss of myelin and can have devastating effects on brain function. We have identified a key factor that is essential for oligodendrocyte generation, known as Kir4.1 channels. The aim of this project is to determine the importance of Kir4.1 in OPCs in the life-long generation of oligodendrocytes and myelin and maintenance of a healthy brain. This will provide new knowledge on the mechanisms controlling the generation of myelin and how this may go wrong in pathology and may ultimately lead to the identification of new cellular targets for protecting the healthy brain.

The proposal is to test the hypothesis that Kir4.1 potassium channels expressed by oligodendrocyte progenitor cells (OPCs) are vitally important for the life-long generation of oligodendrocytes and myelin. Oligodendrocytes are specialised to form myelin in the CNS. Myelin is essential for rapid neuronal connectivity throughout the CNS and underlies the massive computing power of the human brain. Moreover, the myelin sheath is essential for the long-term integrity of myelinated axons. Fate-mapping studies in mice provide direct evidence that myelin is replaced throughout life by oligodendrocytes newly generated from endogenous OPCs. The failure of repair has devastating effects on brain function and neuronal integrity in multiple neuropathologies, including multiple sclerosis, leukodystrophies, stroke and traumatic injury. Hence, knowledge of the mechanisms regulating oligodendrogliogenesis in the adult brain are relevant to understanding the life-long maintenance of healthy myelin and potential mechanisms of neuropathology. The applicants provide new evidence of a fundamental role for the inwardly rectifying potassium channel Kir4.1 in oligodendrogliogenesis and myelination in the mouse brain. To take this work forward, we have developed an inducible Cre/LoxP mouse line that targets Kir4.1 specifically in OPCs. These mice provide a major new advance that provides us with the temporal control of Kir4.1 function specifically in OPCs and enables us to determine the importance of Kir4.1 in the control of the regenerative capacity of OPCs in the developing and adult brain and following damage. This is fundamental research that is relevant to multiple neuropathologies and is in line with the MRC Neurosciences and Mental Health Board themes of 'resilience, repair and replacement' and 'living a long and healthy life'.

The main beneficiaries of the research will be other scientists and clinicians, by providing new knowledge on the mechanisms maintaining a healthy brain throughout life and potential causative factors involved in neuropathophysiology, with particular relevance to multiple sclerosis and other demyelinating diseases.

This research will also be of interest to patient groups, and the wider public. This project will fill an important gap in our knowledge on promoting a healthy brain across the life-course. We will use several routes to engage potential user groups and the general public, by open lab visits to the general public, presenting to local schools, writing articles for magazines, and presenting to the public and patient groups at meetings of Portsmouth MS Society, University of Portsmouth Ageing Network (UPAN), Alzheimer's Research UK (ARUK) Southern Network.

It is not anticipated that any direct commercial benefit will arise from this project, but the longer term plan is to use the information gained in this research to identify new potential therapeutic targets for promoting 'resilience, repair and replacement' in the brain and 'living a long and healthy life', which would ultimately enhance the quality of life and health and have considerable economic benefit.