Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination

In collaboration with Luca Fazio

Multiple Sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system, affecting approximately 2.8 million people worldwide. Profound alterations in neuron-glia signaling and neuroaxonal damage are pathological hallmarks of progressive MS and have been associated with an impaired functional integrity of neuronal circuitry. Notably, disappearance of myelin sheaths and damage to the node of Ranvier (NoR) driven by inflammatory demyelination can result in neuronal hyperexcitability, thereby suggesting an altered expression and distribution of specific ion channels at and around NoR. Given the limitations of the current immune-modulatory therapies and the lack of highly efficacious treatments in preventing neuroaxonal exhaustion, an urgent need to establish alternative approaches emerged. In the last decade, significant improvements in the characterization of ion channel function in MS pawed the way to ion channel modulators as new targeted treatments. However, the underlying mechanisms leading to the emergence of chronic hyperexcitability still need to be fully elucidated.  

Under physiological conditions, maintenance of potassium (K+) homeostasis is critical in stabilizing neuronal excitability and shaping the threshold and frequency of action potential discharge. Axonal Kv7 (outward rectifying) and oligodendroglial Kir4.1 (inward rectifying) K+ channels are key determinant of homeostatic regulation of membrane excitability. During repolarization, opening of neuronal Kv7 channels results in a net efflux of K+ ions from the axolemma into the paranodal space, where K+ is “siphoned” to areas of low K+ concentration by astroglial (AS) and oligodendroglial (OL)-Kir4.1 channels. We provided evidence that this neuron-OL shuttling is impaired in the context of inflammatory demyelination, with OL-Kir4.1 channels being chronically downregulated and Kv7 channels undergoing an early transient upregulation, followed by a downregulation in chronic disease. By combining in-vitro and in-vivo electrophysiological studies, we could demonstrate the emergence of cortical hyperexcitability during peak of disease in the mouse experimental autoimmune encephalomyelitis (EAE) model. We hypothesized that an increased Kv7 channel expression represents an endogenous compensatory response aimed at counteracting neuronal hyperexcitability. However, this mechanism cannot be sustained as disease progresses. Given that neuronal Kv7 channels lend themselves to pharmacological modulation, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener that has shown beneficial effect in the treatment of hyperexcitability-related disorders. RTG application promotes the efflux of K+ ions in the extracellular space, thereby stabilizing K+ homeostasis and reducing neuronal excitability in both human and EAE neurons. Moreover, an early treatment with RTG improved neurological and cognitive symptoms in EAE. Collectively, our study demonstrates that “early” pharmacological modulation of Kv7 channels with RTG stabilizes neuron-OL K+ shuttling and delays clinical progression, thereby representing a promising therapeutic strategy to counteract progressive neurodegeneration in MS and neurological disorders characterized by chronic hyperexcitability. View full article