Inhibition of Kv1.1 channels ameliorates Cu(II)-induced microglial activation and cognitive impairment in mice

Microglia-mediated neuroinflammation plays a critical role in neuronal damage in neurodegenerative disorders such as Alzheimer's disease. Evidence shows that voltage-gated potassium (Kv) channels regulate microglial activation. We previously reported that copper dyshomeostasis causes neuronal injury via activating microglia. This study was designed to explore the role of Kv1.1 channels in copper-evoked microglial neuroinflammation. BV-2 microglial cells were treated with Cu(II). DiBAC4(3) was used to measure membrane potential. Microglial activation and neuronal loss were detected by enzyme-linked immunosorbent assay, Western blotting, and immunostaining. Learning and memory function was assessed with Morris water maze task. Cu(II) caused a hyperpolarized membrane potential in microglial cells, an effect abolished by functional Kv1.1 blockade. Blockade of Kv1.1 and knock-down of Kv1.1 with small interfering RNA repressed Cu(II)-induced microglial production of pro-inflammatory mediators. Also, Kv1.1 inhibition attenuated activation of PI3K/Akt-ERK1/2 signaling pathway and production of mitochondrial reactive oxidative species as well as nuclear factor-κB activation in Cu(II)-stimulated microglia. Moreover, the Cu(II)-caused, microglia-mediated neurotoxicity (indicated by reduced neuronal survival and increased dendritic loss) was attenuated by Kv1.1 knock-down. In an in vivo mouse model, hippocampal injection of Cu(II) caused elevated Kv1.1 mRNA (but not other Kv1 channels) expression and enhanced microglial Kv1.1 immunoreactivity in the hippocampus. Furthermore, blockade of Kv1.1 attenuated Cu(II)-induced microglial activation and neuronal dendritic loss in the hippocampus and learning and memory dysfunction. These findings suggest that inhibition of Kv1.1 ameliorates Cu(II)-induced microglial activation and cognitive impairment. Thus, it might represent a potential molecular target for anti-inflammatory therapy of neurodegenerative disorders.