{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T10:57:10Z","timestamp":1794567430785,"version":"4.9.1"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Professor Sanbing Shen","award":["16\/RC\/3948"],"award-info":[{"award-number":["16\/RC\/3948"]}]},{"name":"Professor Sanbing Shen","award":["16\/RC\/3948"],"award-info":[{"award-number":["16\/RC\/3948"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurosci"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p><jats:italic>NRXN1<\/jats:italic> deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. <jats:italic>NRXN1<\/jats:italic> encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1\u03b1\/\u03b2\/\u03b3. Previous studies on cultured cells show that the short NRXN1\u03b2 primarily exerts excitation effect, whereas the long NRXN1\u03b1 which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of <jats:italic>NRXN1<\/jats:italic>\u03b1 deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying <jats:italic>NRXN1<\/jats:italic>\u03b1<jats:sup>+\/-<\/jats:sup> and showed increased calcium transients in patient neurons.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying <jats:italic>NRXN1<\/jats:italic>\u03b1<jats:sup>+\/-<\/jats:sup> using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>NRXN1\u03b1<\/jats:italic><jats:sup>\ufeff\ufeff+\ufeff\ufeff\/\ufeff\ufeff-<\/jats:sup> cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels\/transporter activity including voltage-gated potassium channels (<jats:italic>GRIN1<\/jats:italic>, <jats:italic>GRIN3B<\/jats:italic>, <jats:italic>SLC17A6<\/jats:italic>, <jats:italic>CACNG3<\/jats:italic>, <jats:italic>CACNA1A<\/jats:italic>, <jats:italic>SHANK1<\/jats:italic>), which are likely to couple with the increased excitability in <jats:italic>NRXN1\u03b1<\/jats:italic><jats:sup>\ufeff\ufeff+\ufeff\ufeff\/\ufeff\ufeff-<\/jats:sup> cortical neurons.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Together with recent evidence of increased calcium transients, our results showed that human <jats:italic>NRXN1\u03b1<\/jats:italic><jats:sup>\ufeff\ufeff+\ufeff\ufeff\/\ufeff\ufeff-<\/jats:sup> isoform deletions altered neuronal excitability and non-synaptic function, and <jats:italic>NRXN1\u03b1<\/jats:italic><jats:sup>\ufeff\ufeff+\ufeff\ufeff\/\ufeff\ufeff-<\/jats:sup> patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12868-021-00661-0","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T08:03:06Z","timestamp":1631692986000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["NRXN1\u03b1+\/- is associated with increased excitability in ASD iPSC-derived neurons"],"prefix":"10.1186","volume":"22","author":[{"given":"Sahar","family":"Avazzadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo R.","family":"Quinlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katya","family":"McDonagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein","family":"Jalali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"McInerney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janusz","family":"Krawczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"O\u2019Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva B.","family":"Forman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally A.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Ennis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"Feerick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangming","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Peeters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dockery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanbing","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"661_CR1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.tins.2007.12.005","volume":"31","author":"DG Amaral","year":"2008","unstructured":"Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137\u201345. https:\/\/doi.org\/10.1016\/j.tins.2007.12.005.","journal-title":"Trends Neurosci"},{"key":"661_CR2","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1192\/bjp.bp.114.160192","volume":"208","author":"T Hirvikoski","year":"2016","unstructured":"Hirvikoski T, Mittendorfer-Rutz E, Boman M, Larsson H, Lichtenstein P, B\u00f6lte S. Premature mortality in autism spectrum disorder. Br J Psychiatry. 2016;208:232\u20138. https:\/\/doi.org\/10.1192\/bjp.bp.114.160192.","journal-title":"Br J Psychiatry"},{"key":"661_CR3","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.ajhg.2007.12.009","volume":"82","author":"CR Marshall","year":"2008","unstructured":"Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477\u201388. https:\/\/doi.org\/10.1016\/j.ajhg.2007.12.009.","journal-title":"Am J Hum Genet"},{"key":"661_CR4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000536","volume":"5","author":"M Bucan","year":"2009","unstructured":"Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009;5: e1000536. https:\/\/doi.org\/10.1371\/journal.pgen.1000536.","journal-title":"PLoS Genet"},{"key":"661_CR5","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrg2484","volume":"10","author":"Z Wang","year":"2009","unstructured":"Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10:57\u201363. https:\/\/doi.org\/10.1038\/nrg2484.","journal-title":"Nat Rev Genet"},{"key":"661_CR6","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1002\/ajmg.b.31063","volume":"153B","author":"MSL Ching","year":"2010","unstructured":"Ching MSL, Shen Y, Tan W-H, Jeste SS, Morrow EM, Chen X, et al. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B, Neuropsychiatr Genet. 2010;153B:937\u201347. https:\/\/doi.org\/10.1002\/ajmg.b.31063.","journal-title":"Am J Med Genet B, Neuropsychiatr Genet"},{"key":"661_CR7","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1002\/ajmg.b.32148","volume":"162B","author":"F B\u00e9na","year":"2013","unstructured":"B\u00e9na F, Bruno DL, Eriksson M, van Ravenswaaij-Arts C, Stark Z, Dijkhuizen T, et al. Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am J Med Genet B, Neuropsychiatr Genet. 2013;162B:388\u2013403. https:\/\/doi.org\/10.1002\/ajmg.b.32148.","journal-title":"Am J Med Genet B, Neuropsychiatr Genet"},{"key":"661_CR8","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1002\/mgg3.105","volume":"2","author":"M Vi\u00f1as-Jornet","year":"2014","unstructured":"Vi\u00f1as-Jornet M, Esteba-Castillo S, Gabau E, Ribas-Vidal N, Baena N, San J, et al. A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion. Mol Genet Genomic Med. 2014;2:512\u201321. https:\/\/doi.org\/10.1002\/mgg3.105.","journal-title":"Mol Genet Genomic Med"},{"key":"661_CR9","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/1471-2350-12-106","volume":"12","author":"A Gregor","year":"2011","unstructured":"Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H, et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med Genet. 2011;12:106. https:\/\/doi.org\/10.1186\/1471-2350-12-106.","journal-title":"BMC Med Genet"},{"key":"661_CR10","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1038\/ejhg.2012.95","volume":"20","author":"CP Schaaf","year":"2012","unstructured":"Schaaf CP, Boone PM, Sampath S, Williams C, Bader PI, Mueller JM, et al. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet. 2012;20:1240\u20137. https:\/\/doi.org\/10.1038\/ejhg.2012.95.","journal-title":"Eur J Hum Genet"},{"key":"661_CR11","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1002\/ajmg.a.35780","volume":"161A","author":"MP Dabell","year":"2013","unstructured":"Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, et al. Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A. 2013;161A:717\u201331. https:\/\/doi.org\/10.1002\/ajmg.a.35780.","journal-title":"Am J Med Genet A"},{"key":"661_CR12","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1111\/epi.12078","volume":"54","author":"RS M\u00f8ller","year":"2013","unstructured":"M\u00f8ller RS, Weber YG, Klitten LL, Trucks H, Muhle H, Kunz WS, et al. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy. Epilepsia. 2013;54:256\u201364. https:\/\/doi.org\/10.1111\/epi.12078.","journal-title":"Epilepsia"},{"key":"661_CR13","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1136\/jmg.2007.054437","volume":"45","author":"FR Zahir","year":"2008","unstructured":"Zahir FR, Baross A, Delaney AD, Eydoux P, Fernandes ND, Pugh T, et al. A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha. J Med Genet. 2008;45:239\u201343. https:\/\/doi.org\/10.1136\/jmg.2007.054437.","journal-title":"J Med Genet"},{"key":"661_CR14","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/ajmg.b.31064","volume":"153B","author":"B Wi\u015bniowiecka-Kowalnik","year":"2010","unstructured":"Wi\u015bniowiecka-Kowalnik B, Nesteruk M, Peters SU, Xia Z, Cooper ML, Savage S, et al. Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am J Med Genet B, Neuropsychiatr Genet. 2010;153B:983\u201393. https:\/\/doi.org\/10.1002\/ajmg.b.31064.","journal-title":"Am J Med Genet B, Neuropsychiatr Genet"},{"key":"661_CR15","doi-asserted-by":"publisher","unstructured":"Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Genetic Risk and Outcome in Psychosis (GROUP) Consortium, Sabatti C, et al. Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet. 2008;83:504\u201310. doi: https:\/\/doi.org\/10.1016\/j.ajhg.2008.09.011.","DOI":"10.1016\/j.ajhg.2008.09.011"},{"key":"661_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000373","volume":"5","author":"AC Need","year":"2009","unstructured":"Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, et al. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet. 2009;5: e1000373. https:\/\/doi.org\/10.1371\/journal.pgen.1000373.","journal-title":"PLoS Genet"},{"key":"661_CR17","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1093\/hmg\/ddn351","volume":"18","author":"D Rujescu","year":"2009","unstructured":"Rujescu D, Ingason A, Cichon S, Pietil\u00e4inen OPH, Barnes MR, Toulopoulou T, et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet. 2009;18:988\u201396. https:\/\/doi.org\/10.1093\/hmg\/ddn351.","journal-title":"Hum Mol Genet"},{"key":"661_CR18","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.biopsych.2013.07.022","volume":"75","author":"G Kirov","year":"2014","unstructured":"Kirov G, Rees E, Walters JTR, Escott-Price V, Georgieva L, Richards AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378\u201385. https:\/\/doi.org\/10.1016\/j.biopsych.2013.07.022.","journal-title":"Biol Psychiatry"},{"key":"661_CR19","doi-asserted-by":"publisher","first-page":"3445","DOI":"10.1073\/pnas.1502849112","volume":"112","author":"Q Yan","year":"2015","unstructured":"Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, et al. Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Proc Natl Acad Sci USA. 2015;112:3445\u201350. https:\/\/doi.org\/10.1073\/pnas.1502849112.","journal-title":"Proc Natl Acad Sci USA"},{"key":"661_CR20","doi-asserted-by":"publisher","first-page":"E1253","DOI":"10.1073\/pnas.1621321114","volume":"114","author":"FH Sterky","year":"2017","unstructured":"Sterky FH, Trotter JH, Lee S-J, Recktenwald CV, Du X, Zhou B, et al. Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand. Proc Natl Acad Sci USA. 2017;114:E1253\u201362. https:\/\/doi.org\/10.1073\/pnas.1621321114.","journal-title":"Proc Natl Acad Sci USA"},{"key":"661_CR21","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/0896-6273(95)90306-2","volume":"14","author":"B Ullrich","year":"1995","unstructured":"Ullrich B, Ushkaryov YA, S\u00fcdhof TC. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron. 1995;14:497\u2013507. https:\/\/doi.org\/10.1016\/0896-6273(95)90306-2.","journal-title":"Neuron"},{"key":"661_CR22","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1126\/science.1621094","volume":"257","author":"YA Ushkaryov","year":"1992","unstructured":"Ushkaryov YA, Petrenko AG, Geppert M, S\u00fcdhof TC. Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science. 1992;257:50\u20136. https:\/\/doi.org\/10.1126\/science.1621094.","journal-title":"Science"},{"key":"661_CR23","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1083\/jcb.201812076","volume":"218","author":"JH Trotter","year":"2019","unstructured":"Trotter JH, Hao J, Maxeiner S, Tsetsenis T, Liu Z, Zhuang X, et al. Synaptic neurexin-1 assembles into dynamically regulated active zone nanoclusters. J Cell Biol. 2019;218:2677\u201398. https:\/\/doi.org\/10.1083\/jcb.201812076.","journal-title":"J Cell Biol"},{"key":"661_CR24","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1074\/jbc.273.3.1705","volume":"273","author":"M Geppert","year":"1998","unstructured":"Geppert M, Khvotchev M, Krasnoperov V, Goda Y, Missler M, Hammer RE, et al. Neurexin I alpha is a major alpha-latrotoxin receptor that cooperates in alpha-latrotoxin action. J Biol Chem. 1998;273:1705\u201310. https:\/\/doi.org\/10.1074\/jbc.273.3.1705.","journal-title":"J Biol Chem"},{"key":"661_CR25","doi-asserted-by":"publisher","first-page":"17998","DOI":"10.1073\/pnas.0910297106","volume":"106","author":"MR Etherton","year":"2009","unstructured":"Etherton MR, Blaiss CA, Powell CM, S\u00fcdhof TC. Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci USA. 2009;106:17998\u20138003. https:\/\/doi.org\/10.1073\/pnas.0910297106.","journal-title":"Proc Natl Acad Sci USA"},{"key":"661_CR26","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.stem.2015.07.017","volume":"17","author":"C Pak","year":"2015","unstructured":"Pak C, Danko T, Zhang Y, Aoto J, Anderson G, Maxeiner S, et al. Human Neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell. 2015;17:316\u201328. https:\/\/doi.org\/10.1016\/j.stem.2015.07.017.","journal-title":"Cell Stem Cell"},{"key":"661_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.schres.2014.02.023","volume":"155","author":"G Todarello","year":"2014","unstructured":"Todarello G, Feng N, Kolachana BS, Li C, Vakkalanka R, Bertolino A, et al. Incomplete penetrance of NRXN1 deletions in families with schizophrenia. Schizophr Res. 2014;155:1\u20137. https:\/\/doi.org\/10.1016\/j.schres.2014.02.023.","journal-title":"Schizophr Res"},{"key":"661_CR28","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.ejmg.2018.07.015","volume":"62","author":"M Al Shehhi","year":"2019","unstructured":"Al Shehhi M, Forman EB, Fitzgerald JE, McInerney V, Krawczyk J, Shen S, et al. NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families. Eur J Med Genet. 2019;62:204\u20139. https:\/\/doi.org\/10.1016\/j.ejmg.2018.07.015.","journal-title":"Eur J Med Genet"},{"key":"661_CR29","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1038\/s41588-019-0539-z","volume":"51","author":"E Flaherty","year":"2019","unstructured":"Flaherty E, Zhu S, Barretto N, Cheng E, Deans PJM, Fernando MB, et al. Neuronal impact of patient-specific aberrant NRXN1\u03b1 splicing. Nat Genet. 2019;51:1679\u201390. https:\/\/doi.org\/10.1038\/s41588-019-0539-z.","journal-title":"Nat Genet"},{"key":"661_CR30","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13229-019-0303-3","volume":"10","author":"S Avazzadeh","year":"2019","unstructured":"Avazzadeh S, McDonagh K, Reilly J, Wang Y, Boomkamp SD, McInerney V, et al. Increased Ca2+ signaling in NRXN1\u03b1+\/- neurons derived from ASD induced pluripotent stem cells. Mol Autism. 2019;10:52. https:\/\/doi.org\/10.1186\/s13229-019-0303-3.","journal-title":"Mol Autism"},{"key":"661_CR31","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1034\/j.1601-183X.2003.00037.x","volume":"2","author":"JLR Rubenstein","year":"2003","unstructured":"Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation\/inhibition in key neural systems. Genes Brain Behav. 2003;2:255\u201367. https:\/\/doi.org\/10.1034\/j.1601-183X.2003.00037.x.","journal-title":"Genes Brain Behav"},{"key":"661_CR32","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nature09146","volume":"466","author":"D Pinto","year":"2010","unstructured":"Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368\u201372. https:\/\/doi.org\/10.1038\/nature09146.","journal-title":"Nature"},{"key":"661_CR33","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.ajhg.2014.03.018","volume":"94","author":"D Pinto","year":"2014","unstructured":"Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677\u201394. https:\/\/doi.org\/10.1016\/j.ajhg.2014.03.018.","journal-title":"Am J Hum Genet"},{"key":"661_CR34","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","volume":"27","author":"SM Chambers","year":"2009","unstructured":"Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275\u201380. https:\/\/doi.org\/10.1038\/nbt.1529.","journal-title":"Nat Biotechnol"},{"key":"661_CR35","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1038\/nprot.2012.116","volume":"7","author":"Y Shi","year":"2012","unstructured":"Shi Y, Kirwan P, Livesey FJ. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc. 2012;7:1836\u201346. https:\/\/doi.org\/10.1038\/nprot.2012.116.","journal-title":"Nat Protoc"},{"key":"661_CR36","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1097\/WCO.0b013e328336eb13","volume":"23","author":"JLR Rubenstein","year":"2010","unstructured":"Rubenstein JLR. Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol. 2010;23:118\u201323. https:\/\/doi.org\/10.1097\/WCO.0b013e328336eb13.","journal-title":"Curr Opin Neurol"},{"key":"661_CR37","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.ajhg.2009.10.004","volume":"85","author":"C Zweier","year":"2009","unstructured":"Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet. 2009;85:655\u201366. https:\/\/doi.org\/10.1016\/j.ajhg.2009.10.004.","journal-title":"Am J Hum Genet"},{"key":"661_CR38","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1002\/ajmg.b.32036","volume":"159B","author":"L Duong","year":"2012","unstructured":"Duong L, Klitten LL, M\u00f8ller RS, Ingason A, Jakobsen KD, Skj\u00f8dt C, et al. Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. Am J Med Genet B, Neuropsychiatr Genet. 2012;159B:354\u20138. https:\/\/doi.org\/10.1002\/ajmg.b.32036.","journal-title":"Am J Med Genet B, Neuropsychiatr Genet"},{"key":"661_CR39","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.1002\/ajmg.a.34255","volume":"155A","author":"V Harrison","year":"2011","unstructured":"Harrison V, Connell L, Hayesmoore J, McParland J, Pike MG, Blair E. Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am J Med Genet A. 2011;155A:2826\u201331. https:\/\/doi.org\/10.1002\/ajmg.a.34255.","journal-title":"Am J Med Genet A"},{"key":"661_CR40","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1111\/epi.12668","volume":"55","author":"C Ohba","year":"2014","unstructured":"Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55:994\u20131000. https:\/\/doi.org\/10.1111\/epi.12668.","journal-title":"Epilepsia"},{"key":"661_CR41","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.eplepsyres.2016.11.002","volume":"129","author":"KM Butler","year":"2017","unstructured":"Butler KM, da Silva C, Shafir Y, Weisfeld-Adams JD, Alexander JJ, Hegde M, et al. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Epilepsy Res. 2017;129:17\u201325. https:\/\/doi.org\/10.1016\/j.eplepsyres.2016.11.002.","journal-title":"Epilepsy Res"},{"key":"661_CR42","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/nn.2359","volume":"12","author":"W Hu","year":"2009","unstructured":"Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009;12:996\u20131002. https:\/\/doi.org\/10.1038\/nn.2359.","journal-title":"Nat Neurosci."},{"key":"661_CR43","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuron.2012.01.007","volume":"73","author":"MHP Kole","year":"2012","unstructured":"Kole MHP, Stuart GJ. Signal processing in the axon initial segment. Neuron. 2012;73:235\u201347. https:\/\/doi.org\/10.1016\/j.neuron.2012.01.007.","journal-title":"Neuron"},{"key":"661_CR44","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/s41598-017-17786-0","volume":"8","author":"JC Wong","year":"2018","unstructured":"Wong JC, Makinson CD, Lamar T, Cheng Q, Wingard JC, Terwilliger EF, et al. Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy. Sci Rep. 2018;8:126. https:\/\/doi.org\/10.1038\/s41598-017-17786-0.","journal-title":"Sci Rep"},{"key":"661_CR45","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1093\/hmg\/ddt043","volume":"22","author":"Z Iqbal","year":"2013","unstructured":"Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet. 2013;22:1960\u201370. https:\/\/doi.org\/10.1093\/hmg\/ddt043.","journal-title":"Hum Mol Genet"},{"key":"661_CR46","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1083\/jcb.143.5.1295","volume":"143","author":"D Zhou","year":"1998","unstructured":"Zhou D, Lambert S, Malen PL, Carpenter S, Boland LM, Bennett V. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol. 1998;143:1295\u2013304. https:\/\/doi.org\/10.1083\/jcb.143.5.1295.","journal-title":"J Cell Biol"},{"key":"661_CR47","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1083\/jcb.200109026","volume":"155","author":"SM Jenkins","year":"2001","unstructured":"Jenkins SM, Bennett V. Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. J Cell Biol. 2001;155:739\u201346. https:\/\/doi.org\/10.1083\/jcb.200109026.","journal-title":"J Cell Biol"},{"key":"661_CR48","doi-asserted-by":"publisher","first-page":"16586","DOI":"10.1523\/JNEUROSCI.2307-13.2013","volume":"33","author":"Y Yang","year":"2013","unstructured":"Yang Y, Vasylyev DV, Dib-Hajj F, Veeramah KR, Hammer MF, Dib-Hajj SD, et al. Multistate structural modeling and voltage-clamp analysis of epilepsy\/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state. J Neurosci. 2013;33:16586\u201393. https:\/\/doi.org\/10.1523\/JNEUROSCI.2307-13.2013.","journal-title":"J Neurosci."},{"key":"661_CR49","doi-asserted-by":"publisher","first-page":"3481","DOI":"10.1093\/hmg\/ddu056","volume":"23","author":"H Lee","year":"2014","unstructured":"Lee H, Lin MA, Kornblum HI, Papazian DM, Nelson SF. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet. 2014;23:3481\u20139. https:\/\/doi.org\/10.1093\/hmg\/ddu056.","journal-title":"Hum Mol Genet"},{"key":"661_CR50","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1002\/ana.24263","volume":"76","author":"A Torkamani","year":"2014","unstructured":"Torkamani A, Bersell K, Jorge BS, Bjork RL, Friedman JR, Bloss CS, et al. De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol. 2014;76:529\u201340. https:\/\/doi.org\/10.1002\/ana.24263.","journal-title":"Ann Neurol"},{"key":"661_CR51","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1083\/jcb.200305018","volume":"162","author":"S Poliak","year":"2003","unstructured":"Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol. 2003;162:1149\u201360. https:\/\/doi.org\/10.1083\/jcb.200305018.","journal-title":"J Cell Biol"},{"key":"661_CR52","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/nn.4037","volume":"18","author":"J Aoto","year":"2015","unstructured":"Aoto J, F\u00f6ldy C, Ilcus SMC, Tabuchi K, S\u00fcdhof TC. Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. Nat Neurosci. 2015;18:997\u20131007. https:\/\/doi.org\/10.1038\/nn.4037.","journal-title":"Nat Neurosci"},{"key":"661_CR53","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.neuron.2017.04.011","volume":"94","author":"LY Chen","year":"2017","unstructured":"Chen LY, Jiang M, Zhang B, Gokce O, S\u00fcdhof TC. Conditional deletion of all neurexins defines diversity of essential synaptic organizer functions for neurexins. Neuron. 2017;94:611-625.e4. https:\/\/doi.org\/10.1016\/j.neuron.2017.04.011.","journal-title":"Neuron"},{"key":"661_CR54","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40092","author":"E Deneault","year":"2019","unstructured":"Deneault E, Faheem M, White SH, Rodrigues DC, Sun S, Wei W, et al. CNTN5-\/+or EHMT2-\/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks. Elife. 2019. https:\/\/doi.org\/10.7554\/eLife.40092.","journal-title":"Elife."},{"key":"661_CR55","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1002\/stem.2423","volume":"34","author":"M Liu","year":"2016","unstructured":"Liu M, Guan Z, Shen Q, Flinter F, Dom\u00ednguez L, Ahn JW, et al. Ulk4 regulates neural stem cell pool. Stem Cells. 2016;34:2318\u201331. https:\/\/doi.org\/10.1002\/stem.2423.","journal-title":"Stem Cells"},{"key":"661_CR56","doi-asserted-by":"publisher","first-page":"7589","DOI":"10.1523\/JNEUROSCI.0621-16.2016","volume":"36","author":"M Liu","year":"2016","unstructured":"Liu M, Guan Z, Shen Q, Lalor P, Fitzgerald U, O\u2019Brien T, et al. Ulk4 is essential for ciliogenesis and CSF flow. J Neurosci. 2016;36:7589\u2013600. https:\/\/doi.org\/10.1523\/JNEUROSCI.0621-16.2016.","journal-title":"J Neurosci"},{"key":"661_CR57","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","volume":"47","author":"D Szklarczyk","year":"2019","unstructured":"Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607\u201313. https:\/\/doi.org\/10.1093\/nar\/gky1131.","journal-title":"Nucleic Acids Res"},{"key":"661_CR58","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498\u2013504. https:\/\/doi.org\/10.1101\/gr.1239303.","journal-title":"Genome Res"}],"container-title":["BMC Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12868-021-00661-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12868-021-00661-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12868-021-00661-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T08:07:38Z","timestamp":1631693258000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurosci.biomedcentral.com\/articles\/10.1186\/s12868-021-00661-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,15]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["661"],"URL":"https:\/\/doi.org\/10.1186\/s12868-021-00661-0","relation":{},"ISSN":["1471-2202"],"issn-type":[{"value":"1471-2202","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,15]]},"assertion":[{"value":"18 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval for the study was obtained from the St. James\u2019s\/Tallaght University Hospital and the Galway University Hospital Clinical Research Ethics Committee. All methods\u00a0were carried out\u00a0in accordance with relevant guidelines and regulations. The informed consent for participation was obtained from all participants\/parent\/guardian.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent for publication was obtained from all participants\/parent\/guardian.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"56"}}