{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:44:39Z","timestamp":1792633479633,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R15NS125560"],"award-info":[{"award-number":["1R15NS125560"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:p>There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in <jats:italic>TSC1<\/jats:italic> result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of <jats:italic>Tsc1<\/jats:italic> selectively in cerebellar Purkinje neurons, referred to here as <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic>, have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> animals. Here, we used cohorts of male and female <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. We determined balance and motor coordination deficits are similar in male and female <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> mice, and that deficits in the firing of <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in <jats:italic>Tsc1<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> males compared to females. These results indicate the selective deletion of <jats:italic>Tsc1<\/jats:italic> in Purkinje neurons differentially impairs cerebellar circuits based on sex.<\/jats:p>","DOI":"10.3389\/fnbeh.2024.1474066","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T06:23:54Z","timestamp":1734416634000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons drives sex-specific behavioral impairments linked to autism"],"prefix":"10.3389","volume":"18","author":[{"given":"Ryan J.","family":"Lawson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Lipovsek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel P.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achintya K.","family":"Jena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna J.","family":"Osko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Ransdell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1002\/cne.903260405","article-title":"A quantitative study of the human cerebellum with unbiased stereological techniques","volume":"326","author":"Andersen","year":"1992","journal-title":"J. Comp. Neurol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.ridd.2012.08.025","article-title":"Pre-school children with suspected autism Spectrum disorders: do girls and boys have the same profiles?","volume":"34","author":"Andersson","year":"2013","journal-title":"Res. Dev. Disabil."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1097\/GIM.0b013e31803068c7","article-title":"Genotype\/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States","volume":"9","author":"Au","year":"2007","journal-title":"Genet. Med."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1093\/brain\/121.5.889","article-title":"A Clinicopathological study of autism","volume":"121","author":"Bailey","year":"1998","journal-title":"Brain J. Neurol."},{"key":"ref5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/1526-968X(200011\/12)28:3\/4<93::AID-GENE10>3.0.CO;2-W","article-title":"Cre recombinase expression in cerebellar purkinje cells","volume":"28","author":"Barski","year":"2000","journal-title":"Genesis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"8.12","DOI":"10.1002\/0471142301.ns0812s15","article-title":"Motor coordination and balance in rodents","volume":"15","author":"Carter","year":"2001","journal-title":"Curr. Prot. Neurosci."},{"key":"ref7","author":"Christensen","year":"2018"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1002\/aur.2305","article-title":"Differences in developmental functioning profiles between male and female preschoolers children with autism spectrum disorder","volume":"13","author":"Craig","year":"2020","journal-title":"Autism Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nm1788","article-title":"Reversal of learning deficits in a Tsc2+\/\u2212 mouse model of tuberous sclerosis","volume":"14","author":"Ehninger","year":"2008","journal-title":"Nat. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","article-title":"Identification and characterization of the tuberous sclerosis gene on chromosome 16","volume":"75","year":"1993","journal-title":"Cell"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0301-0082(00)00025-3","article-title":"Neuroprotection by estradiol","volume":"63","author":"Garcia-Segura","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.tics.2011.07.003","article-title":"Genetics of autism Spectrum disorders","volume":"15","author":"Geschwind","year":"2011","journal-title":"Trends Cogn. Sci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1001\/archneur.1994.00540210068014","article-title":"Estrogen replacement therapy in older women: comparisons between Alzheimer\u2019s disease cases and nondemented control subjects","volume":"51","author":"Henderson","year":"1994","journal-title":"Arch. Neurol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.mcn.2008.09.002","article-title":"Sensorimotor enhancement in mouse mutants lacking the Purkinje cell-specific Gi\/o modulator, Pcp2(L7)","volume":"40","author":"Iscru","year":"2009","journal-title":"Mol. Cell. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"ENEURO.0149-24.2024","DOI":"10.1523\/ENEURO.0149-24.2024","article-title":"Tools for Cre-mediated conditional deletion of Floxed alleles from developing cerebellar Purkinje cells","volume":"11","author":"Jahncke","year":"2024","journal-title":"eNeuro"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"321","DOI":"10.5607\/en.2018.27.5.321","article-title":"Sex-specific behavioral features of rodent models of autism Spectrum disorder","volume":"27","author":"Jeon","year":"2018","journal-title":"Exp. Neurobiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1177\/0883073807309788","article-title":"Characterization of autism in Young children with tuberous sclerosis complex","volume":"23","author":"Jeste","year":"2008","journal-title":"J. Child Neurol."},{"key":"ref19","doi-asserted-by":"publisher","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":"Kalume","year":"2007","journal-title":"J. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"247","DOI":"10.5607\/en.2019.28.2.247","article-title":"Social interaction test in home cage as a novel and ethological measure of social behavior in mice","volume":"28","author":"Kim","year":"2019","journal-title":"Exp. Neurobiol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1093\/hmg\/11.5.525","article-title":"A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells","volume":"11","author":"Kwiatkowski","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13229-020-00412-8","article-title":"Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model","volume":"12","author":"Matas","year":"2021","journal-title":"Mol. Autism"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"5422","DOI":"10.1523\/JNEUROSCI.0955-08.2008","article-title":"Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function","volume":"28","author":"Meikle","year":"2008","journal-title":"J. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/j.1601-183X.2004.00071.x","article-title":"Automated apparatus for quantitation of social approach behaviors in mice","volume":"3","author":"Nadler","year":"2004","journal-title":"Genes Brain Behav."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.neurobiolaging.2022.08.014","article-title":"Evidence of sex differences in cellular senescence","volume":"120","author":"Ng","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1007\/s12311-020-01155-1","article-title":"Consensus paper: cerebellum and social cognition","volume":"19","author":"Overwalle","year":"2020","journal-title":"Cerebellum (London, England)"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/0006-8993(72)90213-2","article-title":"Quantitative histological analysis of the cerebellar cortex in the cat. IV. Mossy Fiber-Purkinje cell numerical transfer","volume":"45","author":"Palkovits","year":"1972","journal-title":"Brain Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s10803-014-2223-6","article-title":"Examination of sex differences in a large sample of young children with autism spectrum disorder and typical development","volume":"45","author":"Reinhardt","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1016\/j.bbrc.2005.04.043","article-title":"L7\/Pcp-2-specific expression of Cre recombinase using Knock-in approach","volume":"331","author":"Saito","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"92","DOI":"10.3389\/fnsys.2014.00092","article-title":"Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia","volume":"8","author":"Stoodley","year":"2014","journal-title":"Front. Syst. Neurosci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1038\/s41593-017-0004-1","article-title":"Altered cerebellar connectivity in autism spectrum disorders and rescue of autism-related behaviors in mice","volume":"20","author":"Stoodley","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"bqab185","DOI":"10.1210\/endocr\/bqab185","article-title":"Neurodegenerative disease: roles for sex, hormones, and oxidative stress","volume":"162","author":"Sumien","year":"2021","journal-title":"Endocrinology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.1007\/s10803-018-3510-4","article-title":"Evaluating sex and age differences in ADI-R and ADOS scores in a large European multi-site sample of individuals with autism spectrum disorder","volume":"48","author":"Tillmann","year":"2018","journal-title":"J. Autism Dev. Disord."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/nature11310","article-title":"Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice","volume":"488","author":"Tsai","year":"2012","journal-title":"Nature"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.celrep.2018.09.039","article-title":"Sensitive periods for cerebellar-mediated autistic-like behaviors","volume":"25","author":"Tsai","year":"2018","journal-title":"Cell Rep."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.neuint.2005.11.011","article-title":"17 Beta-estradiol may affect vulnerability of striatum in a 3-Nitropropionic acid-induced experimental model of Huntington\u2019s disease in ovariectomized rats","volume":"48","author":"T\u00fanez","year":"2006","journal-title":"Neurochem. Int."},{"key":"ref38","article-title":"Neuroanatomy, cerebellar dysfunction","author":"Unverdi","year":"2024"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.neuron.2014.07.016","article-title":"The cerebellum, sensitive periods, and autism","volume":"83","author":"Wang","year":"2014","journal-title":"Neuron"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s10803-013-1913-9","article-title":"Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and Meta-analysis","volume":"44","author":"Wijngaarden-Cremers","year":"2014","journal-title":"J. Autism Dev. Disord."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1177\/08830738040190090701","article-title":"Autism and tuberous sclerosis","volume":"19","author":"Wiznitzer","year":"2004","journal-title":"J. Child Neurol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"104624","DOI":"10.1016\/j.beproc.2022.104624","article-title":"Interspecific differences in sociability, social novelty preference, anxiety-and depression-like behaviors between Brandt\u2019s voles and C57BL\/6J mice","volume":"197","author":"Wu","year":"2022","journal-title":"Behav. Process."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/0471142301.ns0826s56","article-title":"Automated three-chambered social approach task for mice","volume":"8","author":"Yang","year":"2011","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1146109","DOI":"10.3389\/fnmol.2023.1146109","article-title":"Minimal influence of estrous cycle on studies of female mouse behaviors","volume":"16","author":"Zeng","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1523\/JNEUROSCI.5685-08.2009","article-title":"Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten Knock-out mice","volume":"29","author":"Zhou","year":"2009","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2024.1474066\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T06:23:57Z","timestamp":1734416637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2024.1474066\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,17]]},"references-count":46,"alternative-id":["10.3389\/fnbeh.2024.1474066"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2024.1474066","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,17]]},"article-number":"1474066"}}