{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:35:21Z","timestamp":1767180921299,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pbio.3003513","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32271010"],"award-info":[{"award-number":["32271010"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974157"],"award-info":[{"award-number":["81974157"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fund for Jiangsu Province Specially-Appointed Professor"},{"name":"Starting Grant for Excellent Talents in Xuzhou Medical University"},{"name":"Innovative Youth Team Project in Xuzhou Medical University","award":["TD202203"],"award-info":[{"award-number":["TD202203"]}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Amyloid precursor protein (APP)-null mice exhibit significant deficits in motor performance, including reduced grip strength and impaired locomotion; however, the underlying neurophysiological mechanisms remain unclear. In this study, we show that conditional knockdown of APP selectively in Purkinje cells (PCs) recapitulates these motor deficits, while exogenous expression of APP in APP-null mice rescues motor function. Electrophysiological analysis revealed that APP deficiency leads to aberrant firing patterns in PCs and reduces inhibitory synaptic transmission onto neurons of the deep cerebellar nucleus (DCN). We identified a marked reduction in Nav1.6-mediated sodium currents as the key mechanism underlying abnormal action potential firing and propagation in APP-deficient PCs. Importantly, all electrophysiological and behavioral deficits were rescued by PC-specific APP reconstitution. These findings reveal a novel and essential role for APP in cerebellar motor control by regulating Nav1.6 channel activity and PC excitability.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003513","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T18:29:53Z","timestamp":1764008993000},"page":"e3003513","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Amyloid precursor protein modulates cerebellar Purkinje cell activity and motor function through regulation of Nav1.6 currents"],"prefix":"10.1371","volume":"23","author":[{"given":"Miao-Jin","family":"Ji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong-Xuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenhao","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruyuan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin-Yin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinran","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanyao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiantao","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1665-778X","authenticated-orcid":true,"given":"Chao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"issue":"27","key":"pbio.3003513.ref001","doi-asserted-by":"crossref","first-page":"7212","DOI":"10.1523\/JNEUROSCI.1450-06.2006","article-title":"Synapse formation and function is modulated by the amyloid precursor protein","volume":"26","author":"C Priller","year":"2006","journal-title":"J Neurosci"},{"issue":"3","key":"pbio.3003513.ref002","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/ncb1690","article-title":"A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis","volume":"10","author":"Q-H Ma","year":"2008","journal-title":"Nat Cell Biol"},{"issue":"11","key":"pbio.3003513.ref003","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1038\/emboj.2011.119","article-title":"APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP","volume":"30","author":"SW Weyer","year":"2011","journal-title":"EMBO J"},{"issue":"6423","key":"pbio.3003513.ref004","article-title":"Secreted amyloid-\u03b2 precursor protein functions as a GABABR1a ligand to modulate synaptic transmission","volume":"363","author":"HC Rice","year":"2019","journal-title":"Science"},{"key":"pbio.3003513.ref005","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.nlm.2016.08.002","article-title":"Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats","volume":"138","author":"M Xiong","year":"2017","journal-title":"Neurobiol Learn Mem"},{"issue":"3","key":"pbio.3003513.ref006","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S0028-3908(98)00204-4","article-title":"Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein","volume":"38","author":"GR Seabrook","year":"1999","journal-title":"Neuropharmacology"},{"issue":"1","key":"pbio.3003513.ref007","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00401-014-1368-x","article-title":"Acute function of secreted amyloid precursor protein fragment APPs\u03b1 in synaptic plasticity","volume":"129","author":"M Hick","year":"2015","journal-title":"Acta Neuropathol"},{"issue":"4","key":"pbio.3003513.ref008","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/0092-8674(95)90073-X","article-title":"beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity","volume":"81","author":"H Zheng","year":"1995","journal-title":"Cell"},{"issue":"29","key":"pbio.3003513.ref009","doi-asserted-by":"crossref","first-page":"7817","DOI":"10.1523\/JNEUROSCI.1026-07.2007","article-title":"The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice","volume":"27","author":"S Ring","year":"2007","journal-title":"J Neurosci"},{"issue":"5","key":"pbio.3003513.ref010","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nrn.2017.29","article-title":"Not just amyloid: physiological functions of the amyloid precursor protein family","volume":"18","author":"UC M\u00fcller","year":"2017","journal-title":"Nat Rev Neurosci"},{"issue":"5","key":"pbio.3003513.ref011","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1523\/JNEUROSCI.4660-04.2005","article-title":"Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2","volume":"25","author":"P Wang","year":"2005","journal-title":"J Neurosci"},{"key":"pbio.3003513.ref012","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/B978-0-444-63956-1.00006-0","article-title":"Physiology of the cerebellum","volume":"154","author":"E D\u2019Angelo","year":"2018","journal-title":"Handb Clin Neurol"},{"issue":"12","key":"pbio.3003513.ref013","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/dvg.20256","article-title":"Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice","volume":"44","author":"S Goebbels","year":"2006","journal-title":"Genesis"},{"issue":"6","key":"pbio.3003513.ref014","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1111\/j.1460-9568.2007.05434.x","article-title":"The relationship between brain activity and peak grip force is modulated by corticospinal system integrity after subcortical stroke","volume":"25","author":"NS Ward","year":"2007","journal-title":"Eur J Neurosci"},{"issue":"4","key":"pbio.3003513.ref015","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/brain\/40.4.461","article-title":"The symptoms of acute cerebellar injuries due to gunshot injuries","volume":"40","author":"G Holmes","year":"1917","journal-title":"Brain"},{"issue":"1","key":"pbio.3003513.ref016","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1080\/14734220309424","article-title":"Expression and distribution of voltage-gated sodium channels in the cerebellum","volume":"2","author":"KL Schaller","year":"2003","journal-title":"Cerebellum"},{"issue":"41","key":"pbio.3003513.ref017","doi-asserted-by":"crossref","first-page":"11065","DOI":"10.1523\/JNEUROSCI.2162-07.2007","article-title":"Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy","volume":"27","author":"F Kalume","year":"2007","journal-title":"J Neurosci"},{"issue":"4","key":"pbio.3003513.ref018","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0896-6273(00)80969-1","article-title":"Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice","volume":"19","author":"IM Raman","year":"1997","journal-title":"Neuron"},{"issue":"8","key":"pbio.3003513.ref019","doi-asserted-by":"crossref","first-page":"113000","DOI":"10.1016\/j.celrep.2023.113000","article-title":"Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation","volume":"42","author":"CA da Silva","year":"2023","journal-title":"Cell Rep"},{"issue":"2","key":"pbio.3003513.ref020","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0197-0186(99)00108-4","article-title":"Expressions of amyloid precursor protein, synaptophysin and presenilin-1 in the different areas of the developing cerebellum of rat","volume":"36","author":"I Fakla","year":"2000","journal-title":"Neurochem Int"},{"issue":"19","key":"pbio.3003513.ref021","doi-asserted-by":"crossref","first-page":"12048","DOI":"10.1074\/jbc.M114.617092","article-title":"Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression","volume":"290","author":"C Liu","year":"2015","journal-title":"J Biol Chem"},{"key":"pbio.3003513.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2015.05.015","article-title":"Selective transgene expression in cerebellar Purkinje cells and granule cells using adeno-associated viruses together with specific promoters","volume":"1620","author":"Y Kim","year":"2015","journal-title":"Brain Res"},{"key":"pbio.3003513.ref023","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.omtm.2017.07.006","article-title":"Minimal Purkinje cell-specific PCP2\/L7 promoter virally available for rodents and non-human primates","volume":"6","author":"K Nitta","year":"2017","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"19","key":"pbio.3003513.ref024","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2023.08.010","article-title":"Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice","volume":"186","author":"NS de Le\u00f3n Reyes","year":"2023","journal-title":"Cell"},{"issue":"15","key":"pbio.3003513.ref025","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1093\/hmg\/ddy169","article-title":"Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells","volume":"27","author":"EM Perkins","year":"2018","journal-title":"Hum Mol Genet"},{"issue":"6","key":"pbio.3003513.ref026","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s12311-018-0960-3","article-title":"Complex spike wars: a new hope","volume":"17","author":"ML Streng","year":"2018","journal-title":"Cerebellum"},{"issue":"12","key":"pbio.3003513.ref027","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1523\/JNEUROSCI.23-12-04899.2003","article-title":"The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study","volume":"23","author":"ZM Khaliq","year":"2003","journal-title":"J Neurosci"},{"issue":"1","key":"pbio.3003513.ref028","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1038\/s41467-023-38839-1","article-title":"Ant venoms contain vertebrate-selective pain-causing sodium channel toxins","volume":"14","author":"SD Robinson","year":"2023","journal-title":"Nat Commun"},{"key":"pbio.3003513.ref029","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.40101","article-title":"Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity","volume":"8","author":"T Tang","year":"2019","journal-title":"Elife"},{"key":"pbio.3003513.ref030","first-page":"189","article-title":"Quantitative histological analysis of the cerebellar nuclei in the cat. I. Numerical data on cells and on synapses","volume":"28","author":"M Palkovits","year":"1977","journal-title":"Exp Brain Res"},{"issue":"11","key":"pbio.3003513.ref031","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1111\/j.1460-9568.1995.tb00653.x","article-title":"Postsynaptic targets of Purkinje cell terminals in the cerebellar and vestibular nuclei of the rat","volume":"7","author":"CI De Zeeuw","year":"1995","journal-title":"Eur J Neurosci"},{"issue":"5","key":"pbio.3003513.ref032","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/0092-8674(94)90066-3","article-title":"Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene","volume":"79","author":"U M\u00fcller","year":"1994","journal-title":"Cell"},{"issue":"9","key":"pbio.3003513.ref033","doi-asserted-by":"crossref","first-page":"113085","DOI":"10.1016\/j.celrep.2023.113085","article-title":"Persistent Nav1.1 and Nav1.6 currents drive spinal locomotor functions through nonlinear dynamics","volume":"42","author":"B Drouillas","year":"2023","journal-title":"Cell Rep"},{"issue":"15","key":"pbio.3003513.ref034","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1523\/JNEUROSCI.18-15-05869.1998","article-title":"Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons","volume":"18","author":"NY Barnes","year":"1998","journal-title":"J Neurosci"},{"issue":"3","key":"pbio.3003513.ref035","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1177\/1073858418785628","article-title":"Purkinje cell representations of behavior: diary of a busy neuron","volume":"25","author":"LS Popa","year":"2019","journal-title":"Neuroscientist"},{"key":"pbio.3003513.ref036","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0079-6123(01)30020-1","article-title":"The cerebellum as a neuronal prosthesis machine","volume":"130","author":"JP Welsh","year":"2001","journal-title":"Prog Brain Res"},{"issue":"3","key":"pbio.3003513.ref037","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1152\/jn.1990.64.3.698","article-title":"Purkinje cell simple spike activity during grasping and lifting objects of different textures and weights","volume":"64","author":"E Espinoza","year":"1990","journal-title":"J Neurophysiol"},{"issue":"4","key":"pbio.3003513.ref038","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s12311-010-0243-0","article-title":"What features of limb movements are encoded in the discharge of cerebellar neurons?","volume":"10","author":"TJ Ebner","year":"2011","journal-title":"Cerebellum"},{"issue":"3","key":"pbio.3003513.ref039","article-title":"Dynorphin promotes stress-induced depressive behaviors by inhibiting ventral pallidal neurons in rats","volume":"236","author":"M-J Ji","year":"2022","journal-title":"Acta Physiol (Oxf)"},{"issue":"7","key":"pbio.3003513.ref040","article-title":"A role for the cerebellum in motor-triggered alleviation of anxiety","volume":"112","author":"X-Y Zhang","year":"2024","journal-title":"Neuron"},{"issue":"16","key":"pbio.3003513.ref041","article-title":"FAM210A is a novel determinant of bone and muscle structure and strength","volume":"115","author":"K-I Tanaka","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pbio.3003513.ref042","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.bbi.2020.07.027","article-title":"Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia","volume":"89","author":"S-T Xie","year":"2020","journal-title":"Brain Behav Immun"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3003513","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003513","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T19:13:09Z","timestamp":1764616389000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003513"}},"subtitle":[],"editor":[{"given":"Helene","family":"Marie","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3003513","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]}}}