{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:33:44Z","timestamp":1790091224497,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V034758\/1"],"award-info":[{"award-number":["MR\/V034758\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["WT104033AIA"],"award-info":[{"award-number":["WT104033AIA"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["MR\/V034758\/1"],"award-info":[{"award-number":["MR\/V034758\/1"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT104033AIA"],"award-info":[{"award-number":["WT104033AIA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Dominantly inherited missense mutations of the KCNA1 gene, which encodes the KV1.1 potassium channel subunit, cause Episodic Ataxia type 1 (EA1). Although the cerebellar incoordination is thought to arise from abnormal Purkinje cell output, the underlying functional deficit remains unclear. Here we examine synaptic and non-synaptic inhibition of Purkinje cells by cerebellar basket cells in an adult mouse model of EA1. The synaptic function of basket cell terminals was unaffected, despite their intense enrichment for KV1.1-containing channels. In turn, the phase response curve quantifying the influence of basket cell input on Purkine cell output was maintained. However, ultra-fast non-synaptic ephaptic coupling, which occurs in the cerebellar \u2018pinceau\u2019 formation surrounding the axon initial segment of Purkinje cells, was profoundly reduced in EA1 mice in comparison with their wild type littermates. The altered temporal profile of basket cell inhibition of Purkinje cells underlines the importance of Kv1.1 channels for this form of signalling, and may contribute to the clinical phenotype of EA1.<\/jats:p>","DOI":"10.3390\/cells12101382","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T08:28:16Z","timestamp":1684139296000},"page":"1382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Basket to Purkinje Cell Inhibitory Ephaptic Coupling Is Abolished in Episodic Ataxia Type 1"],"prefix":"10.3390","volume":"12","author":[{"given":"Henry G. S.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri M.","family":"Kullmann","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ng1094-136","article-title":"Episodic Ataxia\/Myokymia Syndrome Is Associated with Point Mutations in the Human Potassium Channel Gene, KCNA1","volume":"8","author":"Browne","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/365075a0","article-title":"Heteromultimeric K+ Channels in Terminal and Juxtaparanodal Regions of Neurons","volume":"365","author":"Wang","year":"1993","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0169-328X(96)00120-9","article-title":"Ultrastructural Localization of Shaker-Related Potassium Channel Subunits and Synapse-Associated Protein 90 to Septate-like Junctions in Rat Cerebellar Pinceaux","volume":"42","author":"Laube","year":"1996","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4588","DOI":"10.1523\/JNEUROSCI.14-08-04588.1994","article-title":"Localization of Kv1.1 and Kv1.2, Two K Channel Proteins, to Synaptic Terminals, Somata, and Dendrites in the Mouse Brain","volume":"14","author":"Wang","year":"1994","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12102","DOI":"10.1038\/ncomms12102","article-title":"Action Potential Broadening in a Presynaptic Channelopathy","volume":"7","author":"Begum","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1523\/JNEUROSCI.18-03-00948.1998","article-title":"Patch-Clamp Recordings from Cerebellar Basket Cell Bodies and Their Presynaptic Terminals Reveal an Asymmetric Distribution of Voltage-Gated Potassium Channels","volume":"18","author":"Southan","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/nn1025","article-title":"A Mouse Model of Episodic Ataxia Type-1","volume":"6","author":"Herson","year":"2003","journal-title":"Nat. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/0896-6273(95)90022-5","article-title":"Episodic Ataxia Results from Voltage-Dependent Potassium Channels with Altered Functions","volume":"15","author":"Adelman","year":"1995","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9438","DOI":"10.1523\/JNEUROSCI.1651-12.2012","article-title":"Lack of Molecular-Anatomical Evidence for GABAergic Influence on Axon Initial Segment of Cerebellar Purkinje Cells by the Pinceau Formation","volume":"32","author":"Iwakura","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1083\/jcb.53.2.271","article-title":"Specialized Membrane Junctions between Neurons in the Vertebrate Cerebellar Cortex","volume":"53","author":"Sotelo","year":"1972","journal-title":"J. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nn.3624","article-title":"Ultra-Rapid Axon-Axon Ephaptic Inhibition of Cerebellar Purkinje Cells by the Pinceau","volume":"17","author":"Blot","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6244","DOI":"10.1073\/pnas.77.10.6244","article-title":"Electrical Inhibition of Purkinje Cells in the Cerebellum of the Rat","volume":"77","author":"Korn","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Blot, A., and Barbour, B. (2013). Analysis of the Study of the Cerebellar Pinceau by Korn and Axelrad. bioRxiv, 001123.","DOI":"10.1101\/001123"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11433","DOI":"10.1523\/JNEUROSCI.1346-15.2015","article-title":"Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing","volume":"35","author":"Kole","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1038\/ncomms2626","article-title":"Interstitial Cells of Cajal Integrate Excitatory and Inhibitory Neurotransmission with Intestinal Slow-Wave Activity","volume":"4","author":"Klein","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Amat, S.B., Rowan, M.J.M., Gaffield, M.A., Bonnan, A., Kikuchi, C., Taniguchi, H., and Christie, J.M. (2017). Using C-Kit to Genetically Target Cerebellar Molecular Layer Interneurons in Adult Mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179347"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Martina, M., and Taverna, S. (2014). Patch-Clamp Methods and Protocols, Springer. Methods in Molecular Biology.","DOI":"10.1007\/978-1-4939-1096-0"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jneumeth.2006.02.010","article-title":"Cell-Attached Voltage-Clamp and Current-Clamp Recording and Stimulation Techniques in Brain Slices","volume":"154","author":"Perkins","year":"2006","journal-title":"J. Neurosci. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Phoka, E., Cuntz, H., Roth, A., and H\u00e4usser, M. (2010). A New Approach for Determining Phase Response Curves Reveals That Purkinje Cells Can Act as Perfect Integrators. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000768"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/S0896-6273(00)80379-7","article-title":"Tonic Synaptic Inhibition Modulates Neuronal Output Pattern and Spatiotemporal Synaptic Integration","volume":"19","author":"Clark","year":"1997","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1523\/JNEUROSCI.18-08-02842.1998","article-title":"Episodic Ataxia Mutations in Kv1.1 Alter Potassium Channel Function by Dominant Negative Effects or Haploinsufficiency","volume":"18","author":"Zerr","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/BF00188219","article-title":"An Analysis of HRP-Filled Basket Cell Axons in the Cat\u2019s Cerebellum","volume":"188","author":"Bishop","year":"1993","journal-title":"Anat. Embryol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00235206","article-title":"The Inhibitory Interneurones within the Cerebellar Cortex","volume":"1","author":"Eccles","year":"1966","journal-title":"Exp. Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/s12311-011-0302-1","article-title":"Purkinje Cell-Specific Ablation of CaV2.1 Channels Is Sufficient to Cause Cerebellar Ataxia in Mice","volume":"11","author":"Todorov","year":"2012","journal-title":"Cerebellum"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.cell.2013.05.059","article-title":"Second Cistron in CACNA1A Gene Encodes a Transcription Factor Mediating Cerebellar Development and SCA6","volume":"154","author":"Du","year":"2013","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1113\/jphysiol.2013.264309","article-title":"Kv3.3 Channels Harbouring a Mutation of Spinocerebellar Ataxia Type 13 Alter Excitability and Induce Cell Death in Cultured Cerebellar Purkinje Cells","volume":"592","author":"Irie","year":"2014","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.celrep.2013.06.012","article-title":"FGF14 Regulates Presynaptic Ca2+ Channels and Synaptic Transmission","volume":"4","author":"Yan","year":"2013","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1073\/pnas.1608763114","article-title":"Kv1.1 Channelopathy Abolishes Presynaptic Spike Width Modulation by Subthreshold Somatic Depolarization","volume":"114","author":"Vivekananda","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/j.celrep.2018.07.011","article-title":"Voltage- and Branch-Specific Climbing Fiber Responses in Purkinje Cells","volume":"24","author":"Zang","year":"2018","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4724","DOI":"10.1523\/JNEUROSCI.5602-11.2012","article-title":"Pinceau Organization in the Cerebellum Requires Distinct Functions of Neurofascin in Purkinje and Basket Neurons during Postnatal Development","volume":"32","author":"Buttermore","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Couto, J., Linaro, D., Schutter, E.D., and Giugliano, M. (2015). On the Firing Rate Dependency of the Phase Response Curve of Rat Purkinje Neurons In Vitro. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004112"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e60692","DOI":"10.7554\/eLife.60692","article-title":"Firing Rate-Dependent Phase Responses of Purkinje Cells Support Transient Oscillations","volume":"9","author":"Zang","year":"2020","journal-title":"eLife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0306-4522(76)90127-5","article-title":"A Quantitative Electron Microscopic Study of the Purkinje Cell Axon Initial Segment","volume":"1","author":"Somogyi","year":"1976","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1601-183X.2004.00094.x","article-title":"Genetic Modifiers of the Kv\u03b22-Null Phenotype in Mice","volume":"4","author":"Connor","year":"2005","journal-title":"Genes Brain Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e02536","DOI":"10.7554\/eLife.02536","article-title":"Cerebellar Modules Operate at Different Frequencies","volume":"3","author":"Zhou","year":"2014","journal-title":"eLife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e55569","DOI":"10.7554\/eLife.55569","article-title":"Purkinje Cell Neurotransmission Patterns Cerebellar Basket Cells into Zonal Modules Defined by Distinct Pinceau Sizes","volume":"9","author":"Zhou","year":"2020","journal-title":"eLife"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/s41586-021-03220-z","article-title":"A Transcriptomic Atlas of Mouse Cerebellar Cortex Comprehensively Defines Cell Types","volume":"598","author":"Kozareva","year":"2021","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1016\/j.celrep.2014.04.047","article-title":"Optogenetic Mapping of Cerebellar Inhibitory Circuitry Reveals Spatially Biased Coordination of Interneurons via Electrical Synapses","volume":"7","author":"Kim","year":"2014","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.neuron.2018.09.018","article-title":"Ephaptic Coupling Promotes Synchronous Firing of Cerebellar Purkinje Cells","volume":"100","author":"Han","year":"2018","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/s41593-020-0701-z","article-title":"Climbing Fiber Synapses Rapidly and Transiently Inhibit Neighboring Purkinje Cells via Ephaptic Coupling","volume":"23","author":"Han","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.conb.2014.09.002","article-title":"Ephaptic Coupling to Endogenous Electric Field Activity: Why Bother?","volume":"31","author":"Anastassiou","year":"2015","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.nurt.2007.01.010","article-title":"Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy","volume":"4","author":"Rajakulendran","year":"2007","journal-title":"Neurotherapeutics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1113\/jphysiol.2004.075028","article-title":"Feed-Forward Inhibition Shapes the Spike Output of Cerebellar Purkinje Cells","volume":"563","author":"Mittmann","year":"2005","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1523\/JNEUROSCI.1719-20.2020","article-title":"The Cellular Electrophysiological Properties Underlying Multiplexed Coding in Purkinje Cells","volume":"41","author":"Zang","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1152\/jn.1964.27.6.1138","article-title":"Postsynaptic Inhibition of Cerebellar Purkinje Cells","volume":"27","author":"Andersen","year":"1964","journal-title":"J. Neurophysiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1113\/JP271518","article-title":"Time-Invariant Feed-Forward Inhibition of Purkinje Cells in the Cerebellar Cortex in Vivo","volume":"594","author":"Blot","year":"2016","journal-title":"J. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nn1648","article-title":"Decreases in the Precision of Purkinje Cell Pacemaking Cause Cerebellar Dysfunction and Ataxia","volume":"9","author":"Walter","year":"2006","journal-title":"Nat. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1382\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:34:28Z","timestamp":1760124868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,13]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12101382"],"URL":"https:\/\/doi.org\/10.3390\/cells12101382","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,13]]}}}