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Neurosci."],"accepted":{"date-parts":[[2026,1,8]]},"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:p>\n                    Autosomal dominant mutations in\n                    <jats:italic>FGF14<\/jats:italic>\n                    , which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that regulate high-frequency repetitive firing of cerebellar Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in\n                    <jats:italic>FGF14<\/jats:italic>\n                    into the mouse\n                    <jats:italic>Fgf14<\/jats:italic>\n                    locus (\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S<\/jats:sup>\n                    <\/jats:italic>\n                    ). Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials. A shift from tonic to burst firing was mimicked in wild-type Purkinje neurons by bath application of the Nav channel toxin, tetrodotoxin. Burst firing was also measured in heterozygous\n                    <jats:italic>Fgf14<\/jats:italic>\n                    knock-out (\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) Purkinje neurons, suggesting that the impaired firing of\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S\/+<\/jats:sup>\n                    <\/jats:italic>\n                    Purkinje neurons reflects reduced Nav channel availability, owing to the loss of the iFGF14 protein. Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S\/+<\/jats:sup>\n                    <\/jats:italic>\n                    (and\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) animals and voltage-clamp experiments revealed a hyperpolarizing shift in the voltage dependence of closed-state Nav channel inactivation in\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S\/+<\/jats:sup>\n                    <\/jats:italic>\n                    (and\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) Purkinje neurons. Together, these results indicate that\n                    <jats:italic>Fgf14<\/jats:italic>\n                    haploinsufficiency and reduced Nav channel availability underlie impaired firing in\n                    <jats:italic>\n                      Fgf14\n                      <jats:sup>F145S\/+<\/jats:sup>\n                    <\/jats:italic>\n                    Purkinje neurons.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.2016-24.2026","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T18:50:12Z","timestamp":1768935012000},"page":"e2016242026","update-policy":"https:\/\/doi.org\/10.1523\/jneurosci.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["In Vivo Expression of an SCA27A-Linked\n                    <i>FGF14<\/i>\n                    Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons"],"prefix":"10.1523","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5908-9044","authenticated-orcid":false,"given":"Joseph L.","family":"Ransdell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel P.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maolei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-7629","authenticated-orcid":false,"given":"David M.","family":"Ornitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8334-8499","authenticated-orcid":false,"given":"Jeanne M.","family":"Nerbonne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"2026091114152508000_46.7.e2016242026.1","doi-asserted-by":"crossref","first-page":"e141736","DOI":"10.1172\/jci.insight.141736","article-title":"Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels","volume":"5","author":"Abrams","year":"2020","journal-title":"JCI Insight"},{"key":"2026091114152508000_46.7.e2016242026.2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1598110"},{"key":"2026091114152508000_46.7.e2016242026.3","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202213300"},{"key":"2026091114152508000_46.7.e2016242026.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2663-14.2015"},{"key":"2026091114152508000_46.7.e2016242026.5","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2016.1153203"},{"key":"2026091114152508000_46.7.e2016242026.6","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.063347"},{"key":"2026091114152508000_46.7.e2016242026.7","doi-asserted-by":"publisher","DOI":"10.1002\/mds.20708"},{"key":"2026091114152508000_46.7.e2016242026.8","first-page":"Unit 8.12","article-title":"Motor coordination and balance in rodents","volume":"8","author":"Carter","year":"2001","journal-title":"Curr Protoc Neurosci Chapter"},{"key":"2026091114152508000_46.7.e2016242026.9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s44161-022-00060-6","article-title":"Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current","volume":"1","author":"Chakouri","year":"2022","journal-title":"Nat Cardiovasc Res"},{"key":"2026091114152508000_46.7.e2016242026.10","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-014-0436-7"},{"key":"2026091114152508000_46.7.e2016242026.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2013.10.006"},{"key":"2026091114152508000_46.7.e2016242026.12","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201286"},{"key":"2026091114152508000_46.7.e2016242026.13","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00103"},{"key":"2026091114152508000_46.7.e2016242026.14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.001842"},{"key":"2026091114152508000_46.7.e2016242026.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2005.02.002"},{"key":"2026091114152508000_46.7.e2016242026.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.07.006"},{"key":"2026091114152508000_46.7.e2016242026.17","doi-asserted-by":"crossref","unstructured":"Graves TD , Snell HD , Khodakhah K , Griggs RC , Jen JC (2024) Chapter 8 - the episodic ataxias. 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