Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development Jacob Ellegood, Stela P Petkova, Adrienne Kinman, Lily R Qiu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-90296/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Mar, 2021 Read the published version in Molecular Autism → Version 1 posted 12 You are reading this latest preprint version Abstract Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B ( ARID1B ) , a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created validated to characterize and define neuroanatomical, behavioural and tran­scriptional phenotypes. Neuroanatomy was assess ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones. Results - Brains of adult Arid1b +/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, during neonatal development, Arid1b +/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b +/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b +/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Limitations – The behaviour and the neuroimaging analysis were done on separate cohorts of mice, which does not allow a direct correlation between the imaging and behavioural findings. Conclusions – This study represents a full investigation of Arid1b +/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs. Cellular & Molecular Neuroscience Magnetic Resonance Imaging Coffin-Siris Syndrome Autism Arid1b Mouse Behaviour Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text Cite Share Download PDF Status: Published Journal Publication published 23 Mar, 2021 Read the published version in Molecular Autism → Version 1 posted Review # 3 received at journal 10 Nov, 2020 Editorial decision: Major revision 10 Nov, 2020 Review # 2 received at journal 09 Nov, 2020 Review # 1 received at journal 31 Oct, 2020 Reviewer # 3 agreed at journal 29 Oct, 2020 Reviewers invited by journal 28 Oct, 2020 Reviewer # 1 agreed at journal 28 Oct, 2020 Reviewer # 2 agreed at journal 28 Oct, 2020 Editor assigned by journal 18 Oct, 2020 Editor invited by journal 17 Oct, 2020 Submission checks completed at journal 09 Oct, 2020 First submitted to journal 08 Oct, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-90296","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":3328362,"identity":"d7847a9a-5369-4e7b-87d2-34f443528495","order_by":0,"name":"Jacob Ellegood","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-1504-3321","institution":"Hospital for Sick Children","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Ellegood","suffix":""},{"id":3328363,"identity":"6643710e-be06-425d-b029-782e68b911eb","order_by":1,"name":"Stela P Petkova","email":"","orcid":"","institution":"UC Davis: University of California Davis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stela","middleName":"P","lastName":"Petkova","suffix":""},{"id":3328364,"identity":"fa3eeff1-65ef-4a9d-b77a-86a39e1d12c4","order_by":2,"name":"Adrienne Kinman","email":"","orcid":"","institution":"SickKids: The Hospital for Sick Children","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adrienne","middleName":"","lastName":"Kinman","suffix":""},{"id":3328365,"identity":"8dcbae39-5e1d-4239-935d-8a4235023b7f","order_by":3,"name":"Lily R Qiu","email":"","orcid":"","institution":"Oxford University: University of Oxford","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lily","middleName":"R","lastName":"Qiu","suffix":""},{"id":3328366,"identity":"0c909042-03c9-4b2a-8b8b-f48bbd81b58a","order_by":4,"name":"Ayanna Wade","email":"","orcid":"","institution":"UC Davis: University of California Davis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayanna","middleName":"","lastName":"Wade","suffix":""},{"id":3328367,"identity":"daa27fe1-c583-40bc-98d8-21e969ed5e27","order_by":5,"name":"Darren Fernandes","email":"","orcid":"","institution":"SickKids: The Hospital for Sick Children","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Darren","middleName":"","lastName":"Fernandes","suffix":""},{"id":3328368,"identity":"a201dc8d-7ae4-40c7-a82e-fdd31d99873a","order_by":6,"name":"Zsuzsa Lindenmaier","email":"","orcid":"","institution":"SickKids: The Hospital for Sick Children","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zsuzsa","middleName":"","lastName":"Lindenmaier","suffix":""},{"id":3328369,"identity":"d67ddf25-a065-41dc-8be2-f943b7859905","order_by":7,"name":"Amie Crieghton","email":"","orcid":"","institution":"SickKids: The Hospital for Sick Children","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amie","middleName":"","lastName":"Crieghton","suffix":""},{"id":3328370,"identity":"dac5a71e-404a-4089-acd3-82f805d3d06a","order_by":8,"name":"Lauryl Nutter","email":"","orcid":"","institution":"SickKids: The Hospital for Sick Children","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lauryl","middleName":"","lastName":"Nutter","suffix":""},{"id":3328371,"identity":"ac78829a-2dd5-4c5b-be81-59c582b41893","order_by":9,"name":"Alexander S Nord","email":"","orcid":"","institution":"UC Davis: University of California Davis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"S","lastName":"Nord","suffix":""},{"id":3328372,"identity":"49c598ed-a0ff-492d-bebd-fffae20e3995","order_by":10,"name":"Jill L Silverman","email":"","orcid":"","institution":"UC Davis: University of California Davis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jill","middleName":"L","lastName":"Silverman","suffix":""},{"id":3328373,"identity":"334bf624-7135-4bde-acef-5a08e4129f82","order_by":11,"name":"Jason P Lerch","email":"","orcid":"","institution":"Oxford University: University of Oxford","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jason","middleName":"P","lastName":"Lerch","suffix":""}],"badges":[],"createdAt":"2020-10-09 11:35:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-90296/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-90296/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13229-021-00432-y","type":"published","date":"2021-03-23T15:00:30+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2974913,"identity":"1055ce59-4daa-4534-b0c1-9b695c148684","added_by":"auto","created_at":"2020-10-14 14:55:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95545,"visible":true,"origin":"","legend":"Model Validation (A) Scatterplot of differentially expressed genes in heterozygous\nmice. Genes with p-value \u003c 0.05 are in red. (B) Bar plot indicating logRPKM Arid1b expression\nbetween wild-type (WT) and heterozygous (HT) adult mutants. (C) Table showing select pathways\nenriched in differentially expressed genes meeting an FDR cutoff of 0.2. Pathways enriched in\nup-regulated genes are shown in the peach color. Pathways enriched in down-regulated genes\nare shown in blue. Pathways shown have 500 or fewer genes annotated to their category.\nOntologies are biological pathways (BP), molecular function (MF), or cellular component (CC).","description":"","filename":"Figure1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/36d8ef5f80ba66dbe0de2442.JPG"},{"id":2974914,"identity":"03fc9045-2abb-48b5-80ba-a87d85d9f8dc","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107003,"visible":true,"origin":"","legend":"Structural Differences in Adult Arid1b+/- Mice - Neuroanatomical difference found\nthroughout the brain in the ex vivo adult brain cohort. Shown in both absolute and relative volume\nin the full group, males, and females. Absolute volume differences are measured in mm3, whereas\nrelative volume differences are calculated from a linear model in which the total brain volume is\nused as a covariate.","description":"","filename":"Figure2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/e05aabdb96e4dc6f0c2d8956.JPG"},{"id":2974915,"identity":"56e9ca26-a3c3-4424-b7b7-399d19ca981a","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77885,"visible":true,"origin":"","legend":"Effects of Arid1b+/- on the Brain Throughout Development - A) Highlights the\nresults from the linear mixed effects model. The first column represents the main effect of\ngenotype across the study sample. The next highlights the sex by genotype interaction, followed\nby the age by genotype interaction, and the last column shows the three-way interaction between\nage, sex, and genotype. The growth rates of the B) hippocampal region, C) cerebellum, D) deep\ncerebellar nuclei, and E) fiber tracts are shown throughout development. The trend lines shown\nand the 95% confidence intervals are based on predictions from the linear mixed effects model.","description":"","filename":"Figure3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/43f12a8b78c51750816d0cdc.JPG"},{"id":2974916,"identity":"0e27d74c-b98e-4aa6-8899-34ae1e73b4b0","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":61753,"visible":true,"origin":"","legend":"The effect of Arid1b+/- on the brain differs between sexes - A) Highlights the top 50\nstructures on coronal slices that were larger or smaller in the Arid1b+/- mouse at PND60. The\ndelayed emergence of the differences in the female Arid1b+/- mutants are show for the smaller\n(B) and larger (C) structures. The dotted line shows when significant differences emerge for the\nArid1b+/- mice vs. the WT. The trend lines and the 95% confidence intervals shown are based on\npredictions from the linear mixed effects model.","description":"","filename":"Figure4.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/fae7f40885c44932ca03277f.JPG"},{"id":2974917,"identity":"4632a735-6332-48d9-9a9c-563a06e1889f","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":60286,"visible":true,"origin":"","legend":"Neonatal ultrasonic vocalization emissions, developmental growth, neurological\nreflexes and developmental delays in Arid1b+/-. (A) Across neonatal developmental life,\nArid1b+/- pups displayed abnormal ultrasonic vocalization (USVs) emissions including delay of\npeak number of calls and decreased total number of USVs on several days compared to Arid1b+/+.\n(B) When summed, Arid1b+/- pups emitted significantly fewer USVs compared to Arid1b+/+\nlittermate controls. (C) No genotype difference in axillary abdominal temperature was found,\nconfirming fewer USVs were not the result of neonatal hypothermia. (D) Arid1b+/- weighed less\nacross development beginning at postnatal 8 and continuously throughout development\ncompared to sex-matched Arid1b+/+. (E) Across neonatal developmental life, Arid1b+/- pups were\nshorter by body length (F) and narrower by head width measurements. (G) While Arid1b+/- showed\nnormal latencies to perform the righting reflex, a measure of limb coordination in early life, (H)\nArid1b+/- had prominent deficits in negative geotaxis (i.e., incline reorientation) and (I) the ability\nto traverse out of circle by walking.","description":"","filename":"Figure5.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/3ed7770480201623fa2a6d7d.JPG"},{"id":2974918,"identity":"8d47fd93-2e09-43fc-868c-d517f158f178","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":58221,"visible":true,"origin":"","legend":"Adult Arid1b+/ have diminished physical size, strength and motor ability. (A) Adult\nArid1+/- weigh less compared to Arid1b+/+ adults and throughout behavioural testing. (B) In a\nforelimb grip strength assay, Arid1b+/- showed decreased maximum forelimb force exerted,\nindicating reduced muscle strength. (C-D) Despite their smaller size, Arid1b+/- showed normal\nstride length (C) and stride frequency (D) in fore and hind paws using DigiGait automated gait\nanalysis, indicating normal ambulation and motor coordination of the limbs. (E-H) In open field\nexploration assay, horizontal, vertical and total activity were recorded for a 30-minute period. Data\nare shown over time in 5-minute bins. Arid1b+/- were hypoactive with reduced horizontal activity\n(E), vertical activity (F) and total activity (G). (H) When summed over the 30-minute session,\nArid1b+/- had less total activity compared to Arid1b+/+ (H), indicating a robust motor deficit. For (AB),\nArid1b+/+ N=28, Arid1b+/- N=25, for (C-D) Arid1b+/+ N=21, Arid1b+/+ N=19, for (E-H) Arid1b+/+\nN=28, Arid1b+/- N=26. * p\u003c.05 vs Arid1b+/+ by repeated measures two-way ANOVA or student’s\nunpaired t-test. † p\u003c.09 vs Arid1b+/+ by repeated measures two-way ANOVA. Error bars represent\nmean ±SEM.","description":"","filename":"Figure6.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/631205990528f6e62aab7612.JPG"},{"id":2974919,"identity":"6822bebd-7c0a-4989-98be-0f9389bf179b","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":90363,"visible":true,"origin":"","legend":"Arid1b+/- exhibited mild ASD-relevant social communication phenotypes in the\ndirect reciprocal social interaction and seizure susceptibility but no repetitive behaviour.\nThree-chambered social approach is a standard measure of social behaviour. It was used as a\npreliminary evaluation tool for sociability. While both genotypes exhibited normal social approach\ni.e., they spent more time in the chamber with a novel mouse or time sniffing the novel mouse\ncompared to a novel object), the Arid1b+/- made fewer total entries during the task. (A) Arid1b+/-\nshowed no deficits compared to Arid1b+/+ littermates in 3-chambered social approach in time\nspent in chamber with the novel mouse, (B) time spent sniffing the novel mouse compared to\nnovel object also indicated sociability in both genotypes. (C) Arid1b+/- made fewer transitions compared to Arid1b+/+. (D-F) Next, we moved to a more sensitive task to observe social dyad\ninteractions. During male-female social dyad interactions, males are introduced to a WT, novel\nestrous female for 5 minutes in a novel, clean environment and social investigative and situational\nbehaviours are evaluated and male-emitted ultrasonic vocalizations (USVs) are counted. (D)\nAdult Arid1b+/- males spent less time nose-to-anogenital sniffing and (E) less time in a following\nposture/behaviour, the two main components of this interaction, indicating reduced social\nbehaviour in this task. (F) Arid1b+/- males also emitted fewer USVs during the dyad interactions\ncompared to Arid1b+/+ male littermates which also suggested impaired social communication. (G)\nNo increased or decreased self-grooming was observed. (H-I) We used a gold standard assay of\nanxiety, the elevated plus maze, to observe anxiety-like behaviour. (H) Arid1b+/- spent fewer total\nseconds on the open arm which usually indicates anxiety-like behaviour. (I) Arid1b+/- also showed\nfewer total entries between arms, which suggests this task may be confounded by the data in\nFigure 2, the robust motoric deficit. (J-L) With a high concordance of epilepsy in ASD, and\nexcitatory inhibitory balance being a prominent theory, we investigated seizure susceptibility in\nArid1b+/-. Mice are injected intraperitoneally with pentylenetetrazol (PTZ) chemoconvulsant, and\nlatency to seizure events including loss of righting, tonic-clonic seizure and death were recorded.\n(J) Arid1b+/- showed seizure vulnerability and susceptibility by decreased in time to loss of righting\nafter PTZ administration (K) faster onset to tonic-clonic extension and (L) latency to death,\ncompared to Arid1b+/+. For (A-C), Arid1b+/+ N=28, Arid1b+/- N=25, for (D-F) Arid1b+/+ N=15,\nArid1b+/- N=17, in (G), Arid1b+/+ N=28, Arid1b+/- N=25, for (G-H), Arid1b+/+ N=28, Arid1b+/- N=27,\nfor (J-L), Arid1b+/+ N=45, Arid1b+/- N=40. * p\u003c.05 vs Arid1b+/+ by Repeated Measures Two-Way\nANOVA or Student’s Unpaired t-Test. Error bars represent mean ±SEM.","description":"","filename":"Figure7.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/3e50ea98681fcd00a5601438.JPG"},{"id":2974920,"identity":"dfae1507-b543-4913-9d92-fdfdde8af3e6","added_by":"auto","created_at":"2020-10-14 14:55:41","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":59755,"visible":true,"origin":"","legend":"Largely intact learning and memory in Arid1b+/-. To assess learning and memory\nand behavioural flexibility in a computerized automated task, that does not rely heavily on motor\nskills, we utilized a visual pairwise discrimination touchscreen task. Mice are food-restricted and\ntrained to initiate and execute trials by touching their noses to the touchscreen. Mice are then\ntrained to associate an image (a spider or an airplane, A inset) with a food reward. (A) Arid1b+/-\nrequired fewer sessions to reach criteria of 80% accuracy for two consecutive days compared to\nArid1b+/+ littermates indicated no deficits in ability to acquire visual discrimination. (B) As a\ngroup, Arid1b+/- completed acquisition of the pairwise discrimination task faster than Arid1b+/+,\nwith larger proportions of mice finishing sooner (survival curve). Once animals achieved task\ncriteria, they underwent reversal of the task where the opposite image now becomes the correct\nimage (C, inset). (C-D) Arid1b+/- showed no behavioural inflexibility or deficits in learning and\nmemory in pairwise discrimination reversal compared to Arid1b+/+ by (C) no difference in\nnumber of sessions required to reach criteria (D) and no difference in proportion of mice\nreaching criteria of 75% accuracy for two consecutive days (survival curve, D). (E-F) In a\ncanonical learning and memory tasks with less motor involvement, Pavlovian contextual and auditory cue fear conditioning, Arid1b+/+ and Arid1b+/- demonstrated normal associative learning\nand memory abilities. Learning and memory was assessed by percentage of time spent freezing\nafter associating a context and tone cue with a 0.5 mA foot shock. (E) Arid1b+/- successfully\nacquired fear memory during training and showed intact contextual memory of their environment\n24 hours later. There was no difference in % freezing between Arid1b+/+ and Arid1b+/. (F)\nArid1b+/+ also showed intact cued learning of an auditory tone compared to Arid1b+/+.\nRecognition memory was tested using a novel object recognition test in an open area. Mice are\nhabituated to an open field arena and 24 hours, familiarized for 10 minutes to two identical\nobjects equally spaced in the arena. After an hour long intertrial interval, one object is replaced\nwith a novel one and mice are allowed to explore for 5 minutes. Time spent sniffing the objects\nis recorded. Mice exhibit novel object recognition when they spend more time investigating the\nnovel object compared to the familiar object. (G) Arid1b+/+ successfully showed a preference for\nthe novel object and spent more time sniffing the novel object whereas Arid1b+/- failed to show a\npreference and spent equal time sniffing both objects. For (A-B), Arid1b+/+ N=24, Arid1b+/- N=15,\nfor (C-D), Arid1b+/+ N=20, Arid1b+/- N=14, for (E-F), Arid1b+/+ N=27, Arid1b+/- N=23, for (G),\nArid1b+/+ N=27, Arid1b+/- N=21. * p\u003c.05 vs Arid1b+/+ by repeated measures Two-Way ANOVA or\nStudent’s Unpaired t-Test. Error bars represent mean ±SEM.","description":"","filename":"Figure8.JPG","url":"https://assets-eu.researchsquare.com/files/rs-90296/v1/a3e981d01ba6fe1f424b643e.JPG"}],"financialInterests":"","formattedTitle":"Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-90296/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-autism","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mola","sideBox":"Learn more about [Molecular Autism](http://molecularautism.biomedcentral.com/)","snPcode":"13229","submissionUrl":"https://submission.nature.com/new-submission/13229/3","title":"Molecular Autism","twitterHandle":"@MolecularAutism","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Magnetic Resonance Imaging, Coffin-Siris Syndrome, Autism, Arid1b, Mouse, Behaviour","lastPublishedDoi":"10.21203/rs.3.rs-90296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-90296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground -\u003c/strong\u003e One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (\u003cem\u003eARID1B\u003c/em\u003e) , a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods -\u003c/strong\u003e A novel preclinical mouse model of \u003cem\u003eArid1b \u003c/em\u003edeficiency was created validated to characterize and define neuroanatomical, behavioural and tran­scriptional phenotypes. Neuroanatomy was assess ex vivo in adult animals and in vivo longitudinally from birth to adulthood.\u0026nbsp;Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults - \u003c/strong\u003eBrains of adult \u003cem\u003eArid1b\u003c/em\u003e\u003csup\u003e+/-\u003c/sup\u003e mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume.\u0026nbsp;In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, during neonatal development, \u003cem\u003eArid1b\u003c/em\u003e\u003csup\u003e+/-\u003c/sup\u003e mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, \u003cem\u003eArid1b\u003c/em\u003e\u003csup\u003e+/-\u003c/sup\u003e mice showed low motor skills in open field exploration and normal three chambered approach. \u003cem\u003eArid1b\u003c/em\u003e\u003csup\u003e+/-\u003c/sup\u003e mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLimitations – \u003c/strong\u003eThe behaviour and the neuroimaging analysis were done on separate cohorts of mice, which does not allow a direct correlation between the imaging and behavioural findings. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions –\u003c/strong\u003e This study represents a full investigation of \u003cem\u003eArid1b\u003c/em\u003e\u003csup\u003e\u003cem\u003e+/- \u003c/em\u003e\u003c/sup\u003ehaploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.\u003c/p\u003e","manuscriptTitle":"Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-14 14:55:39","doi":"10.21203/rs.3.rs-90296/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-11-11T00:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"decision","content":"Major revision","date":"2020-11-11T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-11-10T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-01T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-29T12:00:00+00:00","index":3,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-10-28T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-28T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-28T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-10-18T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-17T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-09T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-10-08T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-autism","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mola","sideBox":"Learn more about [Molecular Autism](http://molecularautism.biomedcentral.com/)","snPcode":"13229","submissionUrl":"https://submission.nature.com/new-submission/13229/3","title":"Molecular Autism","twitterHandle":"@MolecularAutism","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0c8a78d0-98e5-4ba3-943d-abda7511c03a","owner":[],"postedDate":"October 14th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":778179,"name":"Cellular \u0026 Molecular Neuroscience"}],"tags":[],"updatedAt":"2021-03-29T15:00:44+00:00","versionOfRecord":{"articleIdentity":"rs-90296","link":"https://doi.org/10.1186/s13229-021-00432-y","journal":{"identity":"molecular-autism","isVorOnly":false,"title":"Molecular Autism"},"publishedOn":"2021-03-23 15:00:30","publishedOnDateReadable":"March 23rd, 2021"},"versionCreatedAt":"2020-10-14 14:55:39","video":"","vorDoi":"10.1186/s13229-021-00432-y","vorDoiUrl":"https://doi.org/10.1186/s13229-021-00432-y","workflowStages":[]},"version":"v1","identity":"rs-90296","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-90296","identity":"rs-90296","version":["v1"]},"buildId":"oE6Zbj460LM0Up2FdVbMZ","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}