{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:37:47Z","timestamp":1777646267356,"version":"3.51.4"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007957","name":"Chongqing Municipal Education Commission","doi-asserted-by":"publisher","award":["KJQN202000410"],"award-info":[{"award-number":["KJQN202000410"]}],"id":[{"id":"10.13039\/501100007957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801506"],"award-info":[{"award-number":["81801506"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004374","name":"Chongqing Medical University","doi-asserted-by":"publisher","award":["SRIEP202003"],"award-info":[{"award-number":["SRIEP202003"]}],"id":[{"id":"10.13039\/501100004374","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive\/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K\/Akt\/GSK-3\u03b2 pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.<\/jats:p>","DOI":"10.1038\/s41398-022-01875-4","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T09:51:13Z","timestamp":1647942673000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Progranulin improves neural development via the PI3K\/Akt\/GSK-3\u03b2 pathway in the cerebellum of a VPA-induced rat model of ASD"],"prefix":"10.1038","volume":"12","author":[{"given":"Lili","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ailing","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junying","family":"Lan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shali","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingbo","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5528-1378","authenticated-orcid":false,"given":"Di","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"1875_CR1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1146\/annurev-publhealth-031816-044318","volume":"38","author":"K Lyall","year":"2017","unstructured":"Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, et al. The changing epidemiology of autism spectrum disorders. Annu Rev Public Health. 2017;38:81\u2013102.","journal-title":"Annu Rev Public Health"},{"key":"1875_CR2","doi-asserted-by":"publisher","first-page":"263","DOI":"10.31887\/DCNS.2012.14.3\/cdoyle","volume":"14","author":"CA Doyle","year":"2012","unstructured":"Doyle CA, McDougle CJ. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan. Dialogues Clin Neurosci. 2012;14:263\u201379.","journal-title":"Dialogues Clin Neurosci"},{"key":"1875_CR3","first-page":"38","volume":"12","author":"L KAJDI","year":"1946","unstructured":"KAJDI L. The treatment of epilepsy in children. Interne. 1946;12:38\u201342.","journal-title":"Interne"},{"key":"1875_CR4","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s12311-014-0627-7","volume":"14","author":"O Baumann","year":"2015","unstructured":"Baumann O, Borra RJ, Bower JM, Cullen KE, Habas C, Ivry RB, et al. Consensus paper: the role of the cerebellum in perceptual processes. Cerebellum. 2015;14:197\u2013220.","journal-title":"Cerebellum"},{"key":"1875_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.pnpbp.2018.04.002","volume":"85","author":"J Moreno-Rius","year":"2018","unstructured":"Moreno-Rius J. The cerebellum in fear and anxiety-related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:23\u201332.","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"1875_CR6","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1146\/annurev.neuro.31.060407.125606","volume":"32","author":"PL Strick","year":"2009","unstructured":"Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413\u201334.","journal-title":"Annu Rev Neurosci"},{"key":"1875_CR7","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1007\/s12311-013-0484-9","volume":"12","author":"SH Fatemi","year":"2013","unstructured":"Fatemi SH. Cerebellum and autism. Cerebellum. 2013;12:778\u20139.","journal-title":"Cerebellum"},{"key":"1875_CR8","doi-asserted-by":"publisher","unstructured":"Becker EBE, Stoodley CJ. Autism spectrum disorder and the cerebellum. 1st ed. Elsevier Inc., 2013 https:\/\/doi.org\/10.1016\/B978-0-12-418700-9.00001-0.","DOI":"10.1016\/B978-0-12-418700-9.00001-0"},{"key":"1875_CR9","doi-asserted-by":"publisher","first-page":"2572","DOI":"10.1093\/brain\/awh287","volume":"127","author":"SJMC Palmen","year":"2004","unstructured":"Palmen SJMC, Van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism. Brain. 2004;127:2572\u201383.","journal-title":"Brain"},{"key":"1875_CR10","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1542\/peds.2007-1041","volume":"120","author":"C Limperopoulos","year":"2007","unstructured":"Limperopoulos C, Bassan H, Gauvreau K, Robertson RL, Sullivan NR, Benson CB, et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics. 2007;120:584\u201393.","journal-title":"Pediatrics"},{"key":"1875_CR11","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1212\/WNL.59.2.184","volume":"59","author":"BF Sparks","year":"2002","unstructured":"Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology. 2002;59:184\u201392.","journal-title":"Neurology"},{"key":"1875_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF02178163","volume":"25","author":"T Hashimoto","year":"1995","unstructured":"Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, et al. Development of the brainstem and cerebellum in autistic patients. J Autism Dev Disord. 1995;25:1\u201318.","journal-title":"J Autism Dev Disord"},{"key":"1875_CR13","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1007\/s00109-003-0474-3","volume":"81","author":"Z He","year":"2003","unstructured":"He Z, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med. 2003;81:600\u201312.","journal-title":"J Mol Med"},{"key":"1875_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1083\/jcb.200712039","volume":"181","author":"P Van Damme","year":"2008","unstructured":"Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, Van Swieten J, et al. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol. 2008;181:37\u201341.","journal-title":"J Cell Biol"},{"key":"1875_CR15","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.ncl.2007.03.005","volume":"25","author":"KA Josephs","year":"2007","unstructured":"Josephs KA. Frontotemporal lobar degeneration. Neurol Clin. 2007;25:683\u201396.","journal-title":"Neurol Clin"},{"key":"1875_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-8-111","volume":"8","author":"LY AL-Ayadhi","year":"2011","unstructured":"AL-Ayadhi LY, Mostafa GA. Low plasma progranulin levels in children with autism. J Neuroinflammation. 2011;8:1\u20136.","journal-title":"J Neuroinflammation"},{"key":"1875_CR17","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.1016\/j.bbadis.2017.07.014","volume":"1863","author":"S Hardt","year":"2017","unstructured":"Hardt S, Heidler J, Albuquerque B, Valek L, Altmann C, Wilken-Schmitz A, et al. Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain. Biochim Biophys Acta. 2017;1863:2727\u201345.","journal-title":"Biochim Biophys Acta"},{"key":"1875_CR18","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1177\/002215540004800713","volume":"48","author":"R Daniel","year":"2000","unstructured":"Daniel R, He Z, Carmichael KP, Halper J, Bateman A. Cellular localization of gene expression for progranulin. J Histochem Cytochem. 2000;48:999\u20131009.","journal-title":"J Histochem Cytochem"},{"key":"1875_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-4-7","volume":"4","author":"Z Ahmed","year":"2007","unstructured":"Ahmed Z, Mackenzie IRA, Hutton ML, Dickson DW. Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation. 2007;4:1\u201313.","journal-title":"J Neuroinflammation"},{"key":"1875_CR20","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1097\/WNR.0000000000000442","volume":"26","author":"T Matsuwaki","year":"2015","unstructured":"Matsuwaki T, Kobayashi A, Mase K, Nakamura K, Nakano SI, Miyoshi T, et al. Possible involvement of the cerebellum in motor-function impairment in progranulin-deficient mice. Neuroreport. 2015;26:877\u201381.","journal-title":"Neuroreport"},{"key":"1875_CR21","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.neuron.2018.01.018","volume":"97","author":"N Uesaka","year":"2018","unstructured":"Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, et al. Retrograde signaling from progranulin to Sort1 counteracts synapse elimination in the developing cerebellum. Neuron. 2018;97:796\u2013805.e5.","journal-title":"Neuron"},{"key":"1875_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnbeh.2018.00182","volume":"12","author":"Q Hou","year":"2018","unstructured":"Hou Q, Wang Y, Li Y, Chen D, Yang F, Wang S. A developmental study of abnormal behaviors and altered GABAergic signaling in the VPA-treated rat model of autism. Front Behav Neurosci. 2018;12:1\u201315.","journal-title":"Front Behav Neurosci"},{"key":"1875_CR23","doi-asserted-by":"publisher","first-page":"108689","DOI":"10.1016\/j.neuropharm.2021.108689","volume":"196","author":"J Lan","year":"2021","unstructured":"Lan J, Hu Y, Wang X, Zheng W, Liao A, Wang S, et al. Abnormal spatiotemporal expression pattern of progranulin and neurodevelopment impairment in VPA-induced ASD rat model. Neuropharmacology. 2021;196:108689.","journal-title":"Neuropharmacology"},{"key":"1875_CR24","doi-asserted-by":"publisher","first-page":"5029","DOI":"10.1073\/pnas.1700477114","volume":"114","author":"G Krabbe","year":"2017","unstructured":"Krabbe G, Minami SS, Etchegaray JI, Taneja P, Djukic B, Davalos D, et al. Microglial NF\u03baB-TNF\u03b1 hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci USA. 2017;114:5029\u201334.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1875_CR25","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1007\/s10803-010-0981-3","volume":"40","author":"KA Fournier","year":"2010","unstructured":"Fournier KA, Hass CJ, Naik SK, Lodha N, Cauraugh JH. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J Autism Dev Disord. 2010;40:1227\u201340.","journal-title":"J Autism Dev Disord"},{"key":"1875_CR26","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1111\/j.1469-8749.2007.00734.x","volume":"49","author":"MA Dziuk","year":"2007","unstructured":"Dziuk MA, Larson JCG, Apostu A, Mahone EM, Denckla MB, Mostofsky SH. Dyspraxia in autism: association with motor, social, and communicative deficits. Dev Med Child Neurol. 2007;49:734\u20139.","journal-title":"Dev Med Child Neurol"},{"key":"1875_CR27","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.neuroscience.2016.10.052","volume":"340","author":"SL Main","year":"2017","unstructured":"Main SL, Kulesza RJ. Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia. Neuroscience. 2017;340:34\u201347.","journal-title":"Neuroscience"},{"key":"1875_CR28","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/s12311-013-0506-7","volume":"13","author":"WT Thach","year":"2014","unstructured":"Thach WT. Does the cerebellum initiate movement? Cerebellum. 2014;13:139\u201350.","journal-title":"Cerebellum"},{"key":"1875_CR29","doi-asserted-by":"crossref","unstructured":"Kilgour AHM, Todd OM, Starr JM. A systematic review of the evidence that brain structure is related to muscle structure and their relationship to brain and muscle function in humans over the lifecourse. 2014.","DOI":"10.1186\/1471-2318-14-85"},{"key":"1875_CR30","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.conb.2011.05.021","volume":"21","author":"M Davare","year":"2011","unstructured":"Davare M, Kraskov A, Rothwell JC, Lemon RN. Interactions between areas of the cortical grasping network. Curr Opin Neurobiol. 2011;21:565\u201370.","journal-title":"Curr Opin Neurobiol"},{"key":"1875_CR31","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1097\/YCO.0000000000000133","volume":"28","author":"RA Vasa","year":"2015","unstructured":"Vasa RA, Mazurek MO. An update on anxiety in youth with autism spectrum disorders. Curr Opin Psychiatry. 2015;28:83\u201390.","journal-title":"Curr Opin Psychiatry"},{"key":"1875_CR32","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.yebeh.2009.02.034","volume":"15","author":"AM Kanner","year":"2009","unstructured":"Kanner AM. Psychiatric issues in epilepsy: the complex relation of mood, anxiety disorders, and epilepsy. Epilepsy Behav. 2009;15:83\u201387.","journal-title":"Epilepsy Behav"},{"key":"1875_CR33","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.yebeh.2005.05.014","volume":"7","author":"S Beyenburg","year":"2005","unstructured":"Beyenburg S, Mitchell AJ, Schmidt D, Elger CE, Reuber M. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav. 2005;7:161\u201371.","journal-title":"Epilepsy Behav"},{"key":"1875_CR34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-016-0028-x","volume":"7","author":"K Zhang","year":"2017","unstructured":"Zhang K, Li YJ, Feng D, Zhang P, Wang YT, Li X, et al. Imbalance between TNF\u03b1 and progranulin contributes to memory impairment and anxiety in sleep-deprived mice. Sci Rep. 2017;7:1\u201312.","journal-title":"Sci Rep"},{"key":"1875_CR35","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/S1734-1140(12)70927-1","volume":"64","author":"B Kumar","year":"2012","unstructured":"Kumar B, Prakash A, Sewal RK, Medhi B, Modi M. Drug therapy in autism: a present and future perspective. Pharm Rep. 2012;64:1291\u2013304.","journal-title":"Pharm Rep"},{"key":"1875_CR36","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ijdevneu.2014.04.004","volume":"36","author":"H Wei","year":"2014","unstructured":"Wei H, Alberts I, Li X. The apoptotic perspective of autism. Int J Dev Neurosci. 2014;36:13\u201318.","journal-title":"Int J Dev Neurosci"},{"key":"1875_CR37","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/ar.10100","volume":"267","author":"WY Chan","year":"2002","unstructured":"Chan WY, Lorke DE, Tiu SC, Yew DT. Proliferation and apoptosis in the developing human neocortex. Anat Rec. 2002;267:261\u201376.","journal-title":"Anat Rec"},{"key":"1875_CR38","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.brainres.2010.09.101","volume":"1380","author":"E Courchesne","year":"2011","unstructured":"Courchesne E, Campbell K, Solso S. Brain growth across the life span in autism: age-specific changes in anatomical pathology. Brain Res. 2011;1380:138\u201345.","journal-title":"Brain Res"},{"key":"1875_CR39","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.neuroscience.2009.10.035","volume":"165","author":"AM Sheikh","year":"2010","unstructured":"Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M. Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects. Neuroscience. 2010;165:363\u201370.","journal-title":"Neuroscience"},{"key":"1875_CR40","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1097\/00001756-200104170-00013","volume":"12","author":"SH Fatemi","year":"2001","unstructured":"Fatemi SH, Halt AR, Stary JM, Realmuto GM, Jalali-Mousavi M. Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum. Neuroreport. 2001;12:929\u201333.","journal-title":"Neuroreport"},{"key":"1875_CR41","doi-asserted-by":"publisher","first-page":"3931","DOI":"10.1002\/cne.22430","volume":"518","author":"TL Petkau","year":"2010","unstructured":"Petkau TL, Neal SJ, Orban PC, MacDonald JL, Hill AM, Lu G, et al. Progranulin expression in the developing and adult murine brain. J Comp Neurol. 2010;518:3931\u201347.","journal-title":"J Comp Neurol"},{"key":"1875_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13024-016-0132-1","volume":"11","author":"C Altmann","year":"2016","unstructured":"Altmann C, Vasic V, Hardt S, Heidler J, H\u00e4ussler A, Wittig I, et al. Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling. Mol Neurodegener. 2016;11:1\u201322.","journal-title":"Mol Neurodegener"},{"key":"1875_CR43","doi-asserted-by":"publisher","first-page":"3955","DOI":"10.1172\/JCI63113","volume":"122","author":"LH Martens","year":"2012","unstructured":"Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012;122:3955\u20139.","journal-title":"J Clin Invest"},{"key":"1875_CR44","doi-asserted-by":"publisher","first-page":"2326.e5","DOI":"10.1016\/j.neurobiolaging.2011.06.017","volume":"32","author":"J Xu","year":"2011","unstructured":"Xu J, Xilouri M, Bruban J, Shioi J, Shao Z, Papazoglou I, et al. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging. 2011;32:2326.e5\u20132326.e16.","journal-title":"Neurobiol Aging"},{"key":"1875_CR45","doi-asserted-by":"publisher","first-page":"4093","DOI":"10.1523\/JNEUROSCI.0827-16.2017","volume":"37","author":"S Liu","year":"2017","unstructured":"Liu S, Zhou L, Yuan H, Vieira M, Sanz-Clemente A, Badger JD, et al. A rare variant identified within the GluN2B C-terminus in a patient with autism affects NMDA receptor surface expression and spine density. J Neurosci. 2017;37:4093\u2013102.","journal-title":"J Neurosci"},{"key":"1875_CR46","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.conb.2012.02.002","volume":"22","author":"SGN Grant","year":"2012","unstructured":"Grant SGN. Synaptopathies: Diseases of the synaptome. Curr Opin Neurobiol. 2012;22:522\u20139.","journal-title":"Curr Opin Neurobiol"},{"key":"1875_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnins.2017.00035","volume":"11","author":"Y Hatanaka","year":"2017","unstructured":"Hatanaka Y, Kabuta T, Wada K. Disturbance in maternal environment leads to abnormal synaptic instability during neuronal circuitry development. Front Neurosci. 2017;11:1\u20137.","journal-title":"Front Neurosci"},{"key":"1875_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2017.00359","volume":"11","author":"J Gilbert","year":"2017","unstructured":"Gilbert J, Man HY. Fundamental elements in autism: from neurogenesis and neurite growth to synaptic plasticity. Front Cell Neurosci. 2017;11:1\u201325.","journal-title":"Front Cell Neurosci"},{"key":"1875_CR49","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.neuron.2014.07.016","volume":"83","author":"SSH Wang","year":"2014","unstructured":"Wang SSH, Kloth AD, Badura A. The cerebellum, sensitive periods, and autism. Neuron. 2014;83:518\u201332.","journal-title":"Neuron"},{"key":"1875_CR50","doi-asserted-by":"publisher","first-page":"10817","DOI":"10.1073\/pnas.0903603106","volume":"106","author":"EB Han","year":"2009","unstructured":"Han EB, Stevens CF. Development regulates a switch between postand presynaptic strengthening in response to activity deprivation. Proc Natl Acad Sci USA. 2009;106:10817\u201322.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1875_CR51","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.nbd.2011.10.016","volume":"45","author":"TL Petkau","year":"2012","unstructured":"Petkau TL, Neal SJ, Milnerwood A, Mew A, Hill AM, Orban P, et al. Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis. 2012;45:711\u201322.","journal-title":"Neurobiol Dis"},{"key":"1875_CR52","doi-asserted-by":"publisher","first-page":"11126","DOI":"10.1523\/JNEUROSCI.6244-10.2011","volume":"31","author":"L Tapia","year":"2011","unstructured":"Tapia L, Milnerwood A, Guo A, Mills F, Yoshida E, Vasuta C, et al. Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. J Neurosci. 2011;31:11126\u201332.","journal-title":"J Neurosci"},{"key":"1875_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pnpbp.2018.08.025","volume":"89","author":"J Moreno-Rius","year":"2019","unstructured":"Moreno-Rius J. Is there an \u201cantisocial\u201d cerebellum? Evidence from disorders other than autism characterized by abnormal social behaviours. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:1\u20138.","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"1875_CR54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2019.00441","volume":"13","author":"JS Gill","year":"2019","unstructured":"Gill JS, Sillitoe RV. Functional outcomes of cerebellar malformations. Front Cell Neurosci. 2019;13:1\u201320.","journal-title":"Front Cell Neurosci"},{"key":"1875_CR55","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1042\/BST0341287","volume":"34","author":"K Frebel","year":"2006","unstructured":"Frebel K, Wiese S. Signalling molecules essential for neuronal survival and differentiation. Biochem Soc Trans. 2006;34:1287\u201390.","journal-title":"Biochem Soc Trans"},{"key":"1875_CR56","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ijdevneu.2014.03.006","volume":"35","author":"J Chen","year":"2014","unstructured":"Chen J, Alberts I, Li X. Dysregulation of the IGF-I\/PI3K\/AKT\/mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci. 2014;35:35\u201341.","journal-title":"Int J Dev Neurosci"},{"key":"1875_CR57","doi-asserted-by":"publisher","first-page":"19929","DOI":"10.1074\/jbc.273.32.19929","volume":"273","author":"M Pap","year":"1998","unstructured":"Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase\/Akt cell survival pathway. J Biol Chem. 1998;273:19929\u201332.","journal-title":"J Biol Chem"},{"key":"1875_CR58","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1007\/s13238-010-0067-1","volume":"1","author":"X Gao","year":"2010","unstructured":"Gao X, Joselin AP, Wang L, Kar A, Ray P, Bateman A, et al. Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3\u03b2. Protein Cell. 2010;1:552\u201362.","journal-title":"Protein Cell"},{"key":"1875_CR59","doi-asserted-by":"publisher","unstructured":"Paushter DH, Du H, Feng T, Hu F. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol. 2018; 136. https:\/\/doi.org\/10.1007\/s00401-018-1861-8.","DOI":"10.1007\/s00401-018-1861-8"},{"key":"1875_CR60","doi-asserted-by":"publisher","unstructured":"Zheng Y, Brady OA, Meng PS, Mao Y, Hu F. C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS ONE 2011; 6. https:\/\/doi.org\/10.1371\/journal.pone.0021023.","DOI":"10.1371\/journal.pone.0021023"},{"key":"1875_CR61","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/j.neuron.2010.09.034","volume":"68","author":"F Hu","year":"2010","unstructured":"Hu F, Padukkavidana T, V\u00e6gter CB, Brady OA, Zheng Y, Mackenzie IR, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68:654\u201367.","journal-title":"Neuron"},{"key":"1875_CR62","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1016\/j.neurobiolaging.2013.04.022","volume":"34","author":"L De Muynck","year":"2013","unstructured":"De Muynck L, Herdewyn S, Beel S, Scheveneels W, Van Den Bosch L, Robberecht W, et al. The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding. Neurobiol Aging. 2013;34:2541\u20137.","journal-title":"Neurobiol Aging"},{"key":"1875_CR63","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1083\/jcb.201502029","volume":"210","author":"X Zhou","year":"2015","unstructured":"Zhou X, Sun L, de Oliveira FB, Qi X, Brown WJ, Smolka MB, et al. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol. 2015;210:991\u20131002.","journal-title":"J Cell Biol"},{"key":"1875_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11992","volume":"7","author":"AM Nicholson","year":"2016","unstructured":"Nicholson AM, Finch NA, Almeida M, Perkerson RB, van Blitterswijk M, Wojtas A, et al. Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun. 2016;7:11992.","journal-title":"Nat Commun"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-022-01875-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-022-01875-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-022-01875-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T19:18:56Z","timestamp":1669231136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-022-01875-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,22]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["1875"],"URL":"https:\/\/doi.org\/10.1038\/s41398-022-01875-4","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,22]]},"assertion":[{"value":"16 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 February 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All experimental animal programs were carried out under the guideline of the Chongqing Management Approach of Laboratory Animal (Chongqing government order No. 195).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"114"}}