Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
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Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination. / Kapell, Hannah; Fazio, Luca; Dyckow, Julia; Schwarz, Sophia; Cruz-Herranz, Andrés; Mayer, Christina; Campos, Joaquin; D Este, Elisa; Möbius, Wiebke; Cordano, Christian; Pröbstel, Anne-Katrin; Gharagozloo, Marjan; Zulji, Amel; Narayanan Naik, Venu; Delank, Anna-Katharina; Cerina, Manuela; Müntefering, Thomas; Lerma-Martin, Celia; Sonner, Jana K; Sin, Jung H; Disse, Paul; Rychlik, Nicole; Sabeur, Khalida; Chavali, Manideep; Srivastava, Rajneesh; Heidenreich, Matthias; Fitzgerald, Kathryn C; Seebohm, Guiscard; Stadelmann, Christine; Hemmer, Bernhard; Platten, Michael; Jentsch, Thomas J; Engelhardt, Maren; Budde, Thomas; Nave, Klaus-Armin; Calabresi, Peter A; Friese, Manuel A; Green, Ari J; Acuna, Claudio; Rowitch, David H; Meuth, Sven G; Schirmer, Lucas.
In: J CLIN INVEST, Vol. 133, No. 7, e164223, 03.04.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination
AU - Kapell, Hannah
AU - Fazio, Luca
AU - Dyckow, Julia
AU - Schwarz, Sophia
AU - Cruz-Herranz, Andrés
AU - Mayer, Christina
AU - Campos, Joaquin
AU - D Este, Elisa
AU - Möbius, Wiebke
AU - Cordano, Christian
AU - Pröbstel, Anne-Katrin
AU - Gharagozloo, Marjan
AU - Zulji, Amel
AU - Narayanan Naik, Venu
AU - Delank, Anna-Katharina
AU - Cerina, Manuela
AU - Müntefering, Thomas
AU - Lerma-Martin, Celia
AU - Sonner, Jana K
AU - Sin, Jung H
AU - Disse, Paul
AU - Rychlik, Nicole
AU - Sabeur, Khalida
AU - Chavali, Manideep
AU - Srivastava, Rajneesh
AU - Heidenreich, Matthias
AU - Fitzgerald, Kathryn C
AU - Seebohm, Guiscard
AU - Stadelmann, Christine
AU - Hemmer, Bernhard
AU - Platten, Michael
AU - Jentsch, Thomas J
AU - Engelhardt, Maren
AU - Budde, Thomas
AU - Nave, Klaus-Armin
AU - Calabresi, Peter A
AU - Friese, Manuel A
AU - Green, Ari J
AU - Acuna, Claudio
AU - Rowitch, David H
AU - Meuth, Sven G
AU - Schirmer, Lucas
PY - 2023/4/3
Y1 - 2023/4/3
N2 - 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.
AB - 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.
U2 - 10.1172/JCI164223
DO - 10.1172/JCI164223
M3 - SCORING: Journal article
C2 - 36719741
VL - 133
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 7
M1 - e164223
ER -
