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EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.

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Title: EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.
Authors: Servettini I; Department of Medicine and Health Science 'V. Tiberio', University of Molise, Campobasso, Italy; Department of Medicine and Surgery, University of Perugia, 06156, Perugia, Italy. Electronic address: ilenio.servettini@unimol.it., Megaro A; Department of Medicine and Surgery, University of Perugia, 06156, Perugia, Italy., Caramia M; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genova, Italy; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy., Sforna L; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy., Michelucci A; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy., Catacuzzeno L; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy. Electronic address: luigi.catacuzzeno@unipg.it.
Source: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2026 Oct; Vol. 1872 (7), pp. 168302. Date of Electronic Publication: 2026 May 25.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE
Imprint Name(s): Original Publication: Amsterdam : Elsevier
MeSH Terms: Kv1.1 Potassium Channel*/genetics , Kv1.1 Potassium Channel*/metabolism , Cerebellum*/metabolism , Cerebellum*/pathology , Cerebellum*/physiopathology , Ataxia*/genetics , Ataxia*/metabolism , Ataxia*/pathology , Ataxia*/physiopathology , Cortical Spreading Depression*, Animals ; Mice ; Humans ; Male ; Mice, Inbred C57BL ; Female ; Myokymia
Abstract: Episodic ataxia type 1 (EA1) is a neurological channelopathy caused by loss-of-function mutations in the KCNA1 gene, which encodes the Kv1.1 α-subunit of voltage-gated potassium channels. Clinically, EA1 is characterized by interictal myokymia and transient episodes of generalized ataxia. While the molecular basis of the disease is well established, the mechanisms underlying the paroxysmal nature of attacks remains unclear. Drawing parallels with migraine with aura, an episodic disorder in which cortical spreading depression (CSD), a propagating wave of neuronal and glial depolarization followed by prolonged suppression of excitability, triggers symptoms, we hypothesized that EA1 may similarly involve an increased susceptibility to cerebellar spreading depression (CeSD), driven by reduced Kv1.1 channel activity and heightened cerebellar excitability. In mouse cerebellar slices exposed to elevated extracellular K+, CeSD displayed several properties distinct from CSD, including sensitivity to AMPA and GABAA receptor antagonists, insensitivity to NMDA receptor blockade, and a markedly slower propagation rate. Notably, cerebellar slices from knock-in (KI) mice carrying the EA1-associated Kv1.1 loss-of-function mutation V408A showed significantly accelerated CeSD propagation and greater spatial spread within the molecular layer compared with wild-type counterparts. Furthermore, cerebellar slices from KI mice exhibited increased susceptibility to CeSD when challenged with elevated extracellular K+. Extracellular and patch-clamp recordings further demonstrated that CeSD induced a transient suppression of cerebellar excitatory transmission at parallel fiber-Purkinje cell synapses, with a duration resembling the temporal profile of EA1 attacks. Collectively, these findings support a central role for CeSD in the pathophysiology of EA1.
(Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
Contributed Indexing: Keywords: Cerebellum; Episodic Ataxia type 1; Kv1.1 channel; Spreading depression
Substance Nomenclature: 147173-20-4 (Kv1.1 Potassium Channel)
SCR Disease Name: Episodic Ataxia, Type 1
Entry Date(s): Date Created: 20260526 Date Completed: 20260708 Latest Revision: 20260708
Update Code: 20260708
DOI: 10.1016/j.bbadis.2026.168302
PMID: 42191098
Database: MEDLINE
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  Data: EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.
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  Data: <searchLink fieldCode="AU" term="%22Servettini+I%22">Servettini I</searchLink>; Department of Medicine and Health Science 'V. Tiberio', University of Molise, Campobasso, Italy; Department of Medicine and Surgery, University of Perugia, 06156, Perugia, Italy. Electronic address: ilenio.servettini@unimol.it.<br /><searchLink fieldCode="AU" term="%22Megaro+A%22">Megaro A</searchLink>; Department of Medicine and Surgery, University of Perugia, 06156, Perugia, Italy.<br /><searchLink fieldCode="AU" term="%22Caramia+M%22">Caramia M</searchLink>; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genova, Italy; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy.<br /><searchLink fieldCode="AU" term="%22Sforna+L%22">Sforna L</searchLink>; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy.<br /><searchLink fieldCode="AU" term="%22Michelucci+A%22">Michelucci A</searchLink>; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy.<br /><searchLink fieldCode="AU" term="%22Catacuzzeno+L%22">Catacuzzeno L</searchLink>; Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy. Electronic address: luigi.catacuzzeno@unipg.it.
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  Data: <searchLink fieldCode="JN" term="%22101731730%22">Biochimica et biophysica acta. Molecular basis of disease</searchLink> [Biochim Biophys Acta Mol Basis Dis] 2026 Oct; Vol. 1872 (7), pp. 168302. <i>Date of Electronic Publication: </i>2026 May 25.
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  Data: <searchLink fieldCode="MM" term="%22Kv1%2E1+Potassium+Channel%22">Kv1.1 Potassium Channel*</searchLink>/<searchLink fieldCode="MM" term="%22Kv1%2E1+Potassium+Channel+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Kv1%2E1+Potassium+Channel%22">Kv1.1 Potassium Channel*</searchLink>/<searchLink fieldCode="MM" term="%22Kv1%2E1+Potassium+Channel+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Cerebellum%22">Cerebellum*</searchLink>/<searchLink fieldCode="MM" term="%22Cerebellum+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Cerebellum%22">Cerebellum*</searchLink>/<searchLink fieldCode="MM" term="%22Cerebellum+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cerebellum%22">Cerebellum*</searchLink>/<searchLink fieldCode="MM" term="%22Cerebellum+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Ataxia%22">Ataxia*</searchLink>/<searchLink fieldCode="MM" term="%22Ataxia+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Ataxia%22">Ataxia*</searchLink>/<searchLink fieldCode="MM" term="%22Ataxia+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Ataxia%22">Ataxia*</searchLink>/<searchLink fieldCode="MM" term="%22Ataxia+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Ataxia%22">Ataxia*</searchLink>/<searchLink fieldCode="MM" term="%22Ataxia+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cortical+Spreading+Depression%22">Cortical Spreading Depression*</searchLink><br /><searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Myokymia%22">Myokymia</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Episodic ataxia type 1 (EA1) is a neurological channelopathy caused by loss-of-function mutations in the KCNA1 gene, which encodes the Kv1.1 α-subunit of voltage-gated potassium channels. Clinically, EA1 is characterized by interictal myokymia and transient episodes of generalized ataxia. While the molecular basis of the disease is well established, the mechanisms underlying the paroxysmal nature of attacks remains unclear. Drawing parallels with migraine with aura, an episodic disorder in which cortical spreading depression (CSD), a propagating wave of neuronal and glial depolarization followed by prolonged suppression of excitability, triggers symptoms, we hypothesized that EA1 may similarly involve an increased susceptibility to cerebellar spreading depression (CeSD), driven by reduced Kv1.1 channel activity and heightened cerebellar excitability. In mouse cerebellar slices exposed to elevated extracellular K<superscript>+</superscript>, CeSD displayed several properties distinct from CSD, including sensitivity to AMPA and GABA<subscript>A</subscript> receptor antagonists, insensitivity to NMDA receptor blockade, and a markedly slower propagation rate. Notably, cerebellar slices from knock-in (KI) mice carrying the EA1-associated Kv1.1 loss-of-function mutation V408A showed significantly accelerated CeSD propagation and greater spatial spread within the molecular layer compared with wild-type counterparts. Furthermore, cerebellar slices from KI mice exhibited increased susceptibility to CeSD when challenged with elevated extracellular K<superscript>+</superscript>. Extracellular and patch-clamp recordings further demonstrated that CeSD induced a transient suppression of cerebellar excitatory transmission at parallel fiber-Purkinje cell synapses, with a duration resembling the temporal profile of EA1 attacks. Collectively, these findings support a central role for CeSD in the pathophysiology of EA1.<br /> (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
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  Data: Declaration of competing interest The authors declare no conflict of interest.
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  Data: <i>Keywords: </i>Cerebellum; Episodic Ataxia type 1; Kv1.1 channel; Spreading depression
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  Data: 147173-20-4 (Kv1.1 Potassium Channel)
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  Data: Episodic Ataxia, Type 1
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        Value: 10.1016/j.bbadis.2026.168302
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        Text: English
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        StartPage: 168302
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        Type: general
      – SubjectFull: Mice
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      – SubjectFull: Humans
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      – SubjectFull: Kv1.1 Potassium Channel genetics
        Type: general
      – SubjectFull: Kv1.1 Potassium Channel metabolism
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      – SubjectFull: Cerebellum metabolism
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      – SubjectFull: Cortical Spreading Depression
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      – TitleFull: EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.
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              Text: 2026 Oct
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