Critical role for the inwardly rectifying potassium channel Kir4.1 in astrocyte and oligodendrocyte functions

The brain contains two kinds of cell, nerves that transmit information, and glial cells, which are essential for nerve cells to function correctly. The two main glial cells are astrocytes and oligodendrocytes. Oligodendrocytes form the myelin sheaths that are critical for rapid transmission of nerve signals. Oligodendrocytes do not develop properly in cerebral palsy and are lost in the demyelinating disease multiple sclerosis, resulting in the debilitating clinical signs of these diseases. Also, during transmission of signals nerves release chemicals which are ?mopped up? up by astrocytes. Disruption of these protective functions of astrocytes results in seizures and nerve death, which occur in epilepsy, stroke, and brain injury. Our work has helped show that a specific glial protein called Kir4.1 is absolutely essential for the specialised functions of glia. In humans, the Kir4.1 gene is linked to general seizure susceptibility, and loss of Kir4.1 causes the loss of myelin and disruption of astrocyte protective functions. Ours is fundamental research into the mechanisms by which Kir4.1 regulate glial cell functions, which will inform on seizure susceptibility, injury, and white matter pathology.

The two main glial cell types in the brain are astrocytes and oligodendrocytes. Oligodendrocytes exclusively form CNS myelin and as such are critical for axonal conduction. Two recognised functions of astrocytes are to take up potassium (K+) and glutamate released during neuronal activity, which if uncorrected causes neuronal depolarization, hyperexcitability, seizures, and eventually neurotoxicity. There is clear evidence that these specialised glial functions depend on Kir4.1 channels, which in the CNS can be considered glial specific ion channels. Kir channels have also been shown to act as critical regulators of cell division, whereby gain of Kir function is correlated with an exit from the cell cycle, and loss of Kir function with re-entry of cells into the cell cycle and gliosis. In humans, the Kir4.1 gene is linked to general seizure susceptibility, and loss of Kir4.1 causes membrane depolarization, a break-down of K+ and glutamate homeostasis, increased seizure susceptibility and hypomyelination. We have shown that astrocytes and oligodendrocytes express Kir4.1 in situ and proof of principle that Kir4.1 are essential in glia has been obtained using Kir4.1 knock out mice. We will now manipulate Kir4.1 expression and function to help determine the mechanisms by which they regulate glial function. Our overall strategy is based on the evidence that Kir4.1 are an important determinant of oligodendrocyte differentiation, myelin loss, and reactive astrogliosis, and our fundamental research into these mechanisms will inform on the pathophysiology of general seizure susceptibility, CNS injury, and white matter pathology.