{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:31:36Z","timestamp":1791325896284,"version":"4.3.1"},"reference-count":55,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"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":["R01MH105610, R01MH108519"],"award-info":[{"award-number":["R01MH105610, R01MH108519"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pten germline haploinsufficient (Pten+\/\u2212) mice, which model macrocephaly\/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical\u2013subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+\/\u2212 mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal \u201chard-wired\u201d connectivity through enhancing synaptic plasticity. Thus, we reared Pten+\/\u2212 mice and their wild-type littermates from weaning under either standard (4\u20135 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9\u201310 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+\/\u2212 mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+\/\u2212 mice and partially rescued increased repetitive behavior in Pten+\/\u2212 males. We found that Pten+\/\u2212 mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+\/\u2212 mice, possibly through normalizing the excitatory synaptic protein abundance.<\/jats:p>","DOI":"10.3390\/genes12091366","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T22:49:51Z","timestamp":1630363791000},"page":"1366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Amy E.","family":"Clipperton-Allen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ori S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon Theron","family":"Page","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1136\/jmg.2004.024646","article-title":"Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations","volume":"42","author":"Butler","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/ajmg.b.30493","article-title":"Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly","volume":"144B","author":"Buxbaum","year":"2007","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/ejhg.2013.114","article-title":"Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly","volume":"22","author":"Hobert","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/aur.1266","article-title":"Macrocephaly as a clinical indicator of genetic subtypes in autism","volume":"6","author":"Klein","year":"2013","journal-title":"Autism Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/aur.132","article-title":"Confirmation study of PTEN mutations among individuals with autism or developmental delays\/mental retardation and macrocephaly","volume":"3","author":"McBride","year":"2010","journal-title":"Autism Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/GIM.0b013e31818fd762","article-title":"The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly","volume":"11","author":"Varga","year":"2009","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13229-017-0182-4","article-title":"Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and\/or autism","volume":"8","author":"Yeung","year":"2017","journal-title":"Mol. Autism"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/mp.2014.125","article-title":"Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism","volume":"20","author":"Frazier","year":"2015","journal-title":"Molec. Psychiat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1093\/hmg\/ddr337","article-title":"A comprehensive functional analysis of PTEN mutations: Implications in tumor- and autism-related syndromes","volume":"20","author":"Oliver","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1136\/jmedgenet-2014-102803","article-title":"Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes","volume":"52","author":"Spinelli","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1002\/ajmg.a.31396","article-title":"Bannayan\u2013Riley\u2013Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation","volume":"140A","author":"Boccone","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1177\/0883073811420296","article-title":"Phosphatase and tensin homolog (PTEN) gene mutations and autism: Literature review and a case report of a patient with Cowden syndrome, autistic disorder, and epilepsy","volume":"27","author":"Conti","year":"2012","journal-title":"J. Child. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/ajmg.1477","article-title":"PTEN mutation in a family with Cowden syndrome and autism","volume":"105","author":"Goffin","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1093\/hmg\/ddu057","article-title":"Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests","volume":"23","author":"Page","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/gbb.12192","article-title":"Decreased aggression and increased repetitive behavior in Pten haploinsufficient mice","volume":"14","author":"Page","year":"2015","journal-title":"Genes Brain Behav."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"a037010","DOI":"10.1101\/cshperspect.a037010","article-title":"Connecting genotype with behavioral phenotype in mouse models of autism associated with PTEN mutations","volume":"10","author":"Page","year":"2020","journal-title":"Cold Spring Harb Perspect Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1073\/pnas.0804428106","article-title":"Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior","volume":"106","author":"Page","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5, American Psychiatric Association.","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10252","DOI":"10.1523\/JNEUROSCI.5272-14.2015","article-title":"Pten mutations alter brain growth trajectory and allocation of cell types through elevated beta-catenin signaling","volume":"35","author":"Chen","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41398-019-0656-6","article-title":"Pten haploinsufficiency disrupts scaling across brain areas during development in mice","volume":"9","author":"Cohen","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13421","DOI":"10.1038\/ncomms13421","article-title":"Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly\/autism syndrome","volume":"7","author":"Huang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/aur.2186","article-title":"Genetic suppression of mTOR rescues synaptic and social behavioral abnormalities in a mouse model of Pten haploinsufficiency","volume":"12","author":"Huang","year":"2019","journal-title":"Autism Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.jaac.2017.03.013","article-title":"What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis","volume":"56","author":"Loomes","year":"2017","journal-title":"J. Am. Acad Child. Adolesc. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.dhjo.2009.07.001","article-title":"Sex differences in the evaluation and diagnosis of autism spectrum disorders among children","volume":"3","author":"Giarelli","year":"2010","journal-title":"Disabil Health J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1007\/s00127-010-0294-z","article-title":"Social and demographic factors that influence the diagnosis of autistic spectrum disorders","volume":"46","author":"Russell","year":"2011","journal-title":"Soc. Psychiatry Psychiatr. Epidemiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S1364-6613(02)01904-6","article-title":"The extreme male brain theory of autism","volume":"6","year":"2002","journal-title":"Trends Cogn. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ajhg.2014.02.001","article-title":"A higher mutational burden in females supports a \"female protective model\" in neurodevelopmental disorders","volume":"94","author":"Jacquemont","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1203\/00006450-200001000-00006","article-title":"Imprinting, the X-chromosome, and the male brain: Explaining sex differences in the liability to autism","volume":"47","author":"Skuse","year":"2000","journal-title":"Pediatr. Res."},{"key":"ref_29","unstructured":"Autism Science Foundation (2021, April 13). What is Autism? Treatment Options. Available online: https:\/\/autismsciencefoundation.org\/what-is-autism\/treatment-options\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1007\/s10803-015-2407-8","article-title":"Naturalistic developmental behavioral interventions: Empirically validated treatments for autism spectrum disorder","volume":"45","author":"Schreibman","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.biopsych.2009.12.022","article-title":"Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice","volume":"67","author":"Lonetti","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/npp.2014.291","article-title":"Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome","volume":"40","author":"Oddi","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neubiorev.2019.02.003","article-title":"Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders","volume":"110","author":"More","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nrn1970","article-title":"Enriched environments, experience-dependent plasticity and disorders of the nervous system","volume":"7","author":"Nithianantharajah","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"62","DOI":"10.3389\/fnmol.2016.00062","article-title":"Effects of long-term environmental enrichment on anxiety, memory, hippocampal plasticity and overall brain gene expression in C57BL6 mice","volume":"9","author":"Huttenrauch","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/35044558","article-title":"Neural consequences of environmental enrichment","volume":"1","author":"Kempermann","year":"2000","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1756-6606-2-11","article-title":"Enhanced synaptic long-term potentiation in the anterior cingulate cortex of adult wild mice as compared with that in laboratory mice","volume":"2","author":"Zhao","year":"2009","journal-title":"Mol. Brain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1073\/pnas.96.4.1563","article-title":"Mutation of Pten\/Mmac1 in mice causes neoplasia in multiple organ systems","volume":"96","author":"Podsypanina","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/aur.1641","article-title":"Autism-relevant behaviors are minimally impacted by conditional deletion of Pten in oxytocinergic neurons","volume":"9","author":"Chen","year":"2016","journal-title":"Autism Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/neuro.08.048.2009","article-title":"Computerized assessment of social approach behavior in mouse","volume":"3","author":"Page","year":"2009","journal-title":"Front. Behav. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.bbrc.2010.04.165","article-title":"Impairment of social and emotional behaviors in Cadm1-knockout mice","volume":"396","author":"Takayanagi","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00213-009-1466-y","article-title":"Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety","volume":"204","author":"Thomas","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sejourne, J., Llaneza, D., Kuti, O.J., and Page, D.T. (2015). Social behavioral deficits coincide with the onset of seizure susceptibility in mice lacking serotonin receptor 2c. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136494"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"172955","DOI":"10.1016\/j.pbb.2020.172955","article-title":"Environmental enrichment modulates affiliative and aggressive social behaviour in the neuroligin-3 R451C mouse model of autism spectrum disorder","volume":"195","author":"Burrows","year":"2020","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.bbi.2017.04.009","article-title":"Early enriched physical environment reverses impairments of the hippocampus, but not medial prefrontal cortex, of socially-isolated mice","volume":"64","author":"Cao","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/0031-9384(94)90341-7","article-title":"Effects of environmental enrichment on aggressive behavior, dominance hierarchies, and endocrine states in male DBA\/2J mice","volume":"56","author":"Haemisch","year":"1994","journal-title":"Physiol. Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/ab.21481","article-title":"Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice","volume":"39","author":"Redolat","year":"2013","journal-title":"Aggress Behav."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0031-9384(01)00425-5","article-title":"Modulation of aggression in male mice: Influence of group size and cage size","volume":"72","author":"Mol","year":"2001","journal-title":"Physiol. Behav."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.mad.2011.04.006","article-title":"Continuous enriched environment improves learning and memory in adult NMRI mice through theta burst-related-LTP independent mechanisms but is not efficient in advanced aged animals","volume":"132","author":"Bouet","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1038\/npp.2015.44","article-title":"Environmental enrichment ameliorates behavioral impairments modeling schizophrenia in mice lacking metabotropic glutamate receptor 5","volume":"40","author":"Burrows","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bbr.2014.03.024","article-title":"Enrichment and individual housing reinforce the differences in aggressiveness and amphetamine response in 129S6\/SvEv and C57BL\/6 strains","volume":"267","author":"Heinla","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.neuroscience.2020.07.004","article-title":"Enriched environment rearing from birth reduced anxiety, improved learning and memory, and promoted social interactions in adult male mice","volume":"442","author":"Zheng","year":"2020","journal-title":"Neuroscience"},{"key":"ref_53","first-page":"637","article-title":"Mouse models in aging research","volume":"Volume 3","author":"Fox","year":"2007","journal-title":"The Mouse in Biomedical Research"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2013.04.001","article-title":"Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species","volume":"106\u2013107","author":"Semple","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.biopsych.2016.05.011","article-title":"Excitation\/inhibition imbalance in animal models of autism spectrum disorders","volume":"81","author":"Lee","year":"2017","journal-title":"Biol. Psychiatry"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1366\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:52:49Z","timestamp":1760165569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":55,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091366"],"URL":"https:\/\/doi.org\/10.3390\/genes12091366","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]}}}