Histopathological studies confirm the prominent deposition of immunoglobulins (Ig) and the complement activation in acute demyelinating lesions of multiple sclerosis (MS) patients, suggesting that, at least in a subgroup of MS patients, autoantibodies could contribute to the disease. Recently, the ATP-sensitive inward rectifying potassium channel KIR4.1 has been identified as an antibody target in a small cohort of MS patients, since anti-KIR4.1 antibodies (Abs) were found in the serum of MS patients compared to those with other neurological disorders and healthy donors. Indeed, enhanced KIR4.1 expression was reported either in the brains of cuprizone-induced demyelination mouse model and in reactive astrocytes present at the borders of active MS lesions, suggesting that an abnormal KIR4.1 expression in inflamedMS brainsmight facilitate autoimmune sensitization against this channel. In the current study, we further investigated KIR4.1 expression in association with astrogliosis (GFAP), oligodendrocyte loss (MBP, CNPase) and neurodegeneration (beta-tubulin) in the cuprizone demyelinating model. C57BL/6 male mice were fed with cuprizone (0.2% w/w) for 5 weeks to induce acute demyelination. As control, agematched mice received normal chow diet. We observed a strong localization of KIR4.1 on GFAP-positive astrocytes in the cortex of mouse brain sections. Furthermore, serial brain sections from cuprizone-fed and control mice were immunostained with an MS serum resulted positive for anti-KIR4.1 Ab by ELISA assay using synthetic KIR4.1 peptides; confocal microscopy analysis showed a comparable immunolabelling pattern between MS serum and polyclonal KIR4.1 antibodies, suggesting that the KIR4.1-Abs in the MS serum indeed react with the native KIR4.1 antigen. KIR4.1 expression has also been investigated in experimental autoimmune encephalitis. Our data point further support the possible involvement of KIR4.1 as a candidate autoantigen in MS and are in line with recent reports. In this context, it might be relevant to address whether ‘danger’ signals alter KIR4.1 expression, as might occur in the inflammatory response to Theiler's virus-induced demyelination model.