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Reduced dosage of <jats:italic>Cyfip1<\/jats:italic> is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1\u2013BP2) copy number variant: deletion carriers are haploinsufficient for <jats:italic>CYFIP1<\/jats:italic> and exhibit a two- to four-fold increased risk of schizophrenia, autism and\/or intellectual disability. Here, we model the contributions of <jats:italic>Cyfip1<\/jats:italic> to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that <jats:italic>Cyfip1<\/jats:italic> heterozygous rats (<jats:italic>Cyfip1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, <jats:italic>Cyfip1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult <jats:italic>Cyfip1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate <jats:italic>Cyfip1<\/jats:italic> in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.<\/jats:p>","DOI":"10.1038\/s41398-024-02969-x","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T11:02:15Z","timestamp":1718362935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5975-813X","authenticated-orcid":false,"given":"Josephine E.","family":"Haddon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Titherage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia R.","family":"Heckenast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4798-0862","authenticated-orcid":false,"given":"Michael J.","family":"Owen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0403-3278","authenticated-orcid":false,"given":"Jeremy","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence S.","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5396-3108","authenticated-orcid":false,"given":"Matthew W.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"2969_CR1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature07229","volume":"455","author":"H Stefansson","year":"2008","unstructured":"Stefansson H, Rujescu D, Cichon S, Pietil\u00e4inen OP, Ingason A, Steinberg S, et al. 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