ABSTRACT
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Mice , Animals , Humans , Ranvier's Nodes/metabolism , Potassium/metabolism , Neurons/metabolism , Oligodendroglia/metabolism , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolismABSTRACT
INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system associated with lesions of the cortical gray matter and subcortical white matter. Recently, cortical lesions have become a major focus of research because cortical pathology and neuronal damage are critical determinants of irreversible clinical progression. Recent transcriptomic studies point toward cell type-specific changes in cortical neurons in MS with a selective vulnerability of excitatory projection neuron subtypes. AREAS COVERED: We discuss the cortical mapping and the molecular properties of excitatory projection neurons and their role in MS lesion pathology while placing an emphasis on their subtype-specific transcriptomic changes and levels of vulnerability. We also examine the latest magnetic resonance imaging techniques to study cortical MS pathology as a key tool for monitoring disease progression and treatment efficacy. Finally, we consider possible therapeutic avenues and novel strategies to protect excitatory cortical projection neurons. Literature search methodology: PubMed articles from 2000-2020. EXPERT OPINION: Excitatory cortical projection neurons are an emerging therapeutic target in the treatment of progressive MS. Understanding neuron subtype-specific molecular pathologies and their exact spatial mapping will help establish starting points for the development of novel cell type-specific therapies and biomarkers in MS.
