Function of potassium channel Kir4.1 in oligodendrocyte development and pathology

• Applicant: Professor Dr. Lucas Schirmer
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267660669

Kir4.1 (KCNJ10) is expressed in a subset of astrocytes and oligodendrocytes (OLs) and assumed to be the main inward rectifying potassium channel and important regulator of water and potassium homeostasis in the central nervous system (CNS); mutations of KCNJ10 result in epilepsy and neonatal encephalopathy. In addition, KIR4.1 expressed in OLs shows a strong disease connection to multiple sclerosis (MS). OL KIR4.1 comprises a homotetramer channel, whereas in astrocytes it forms homo- and heterotetramer channels together with KIR5.1. Knockout (KO) studies have suggested an important role of Kir4.1 in glial development and buffering of extracellular and otherwise toxic potassium levels. In humans, we have identified autoantibodies against KIR4.1 in a subset of MS patients. In acute and chronic active MS lesions, KIR4.1 proteins are differentially lost in OLs and astrocytes. The overall objective of this study is to determine the function of Kir4.1 during OL development and under pathological conditions. In Aim 1, we will determine the precise expression pattern of Kir4.1 during CNS development in mouse and human brain. For murine analysis, OL-specific reporter strains will be used, whereas for human, we will take advantage of specimens in the UCSF Neuropathology Research Brain Bank. We will next use conditional KO (cKO) models, deleting Kir4.1 specifically in cells of OL lineage to determine possible functions during OL development, myelination and supporting white matter integrity. In Aim 2, we propose to investigate functions of OL Kir4.1 under pathological conditions. Specifically, we will induce lysolecithin-demyelinated lesions in cKO mice to study the role of Kir4.1 in remyelination. Finally (Aim 3), we will investigate functional effects of KIR4.1 autoantibodies (against a conserved region of Kir4.1) and known Kir4.1 channel inhibitors in cerebellar explant myelination and remyelination assays. These studies are intended to test the hypothesis that Kir4.1 is pivotal in OL differentiation and essential for axon and myelin integrity under normal and pathological demyelinating conditions.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David Rowitch, Ph.D.