Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility.

Autor: Haddon JE; Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, UK. HaddonJE2@cardiff.ac.uk.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, UK. HaddonJE2@cardiff.ac.uk., Titherage D; School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.; Centre for Academic Mental Health, Population Health sciences, University of Bristol, Bristol, UK., Heckenast JR; School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK., Carter J; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, UK., Owen MJ; Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, UK.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, UK.; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK., Hall J; Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, UK.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, UK.; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK., Wilkinson LS; Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, UK.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, UK.; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.; School of Psychology, Cardiff University, Cardiff, UK., Jones MW; School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2024 Jun 14; Vol. 14 (1), pp. 256. Date of Electronic Publication: 2024 Jun 14.
DOI: 10.1038/s41398-024-02969-x
Abstrakt: Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 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 Cyfip1 heterozygous rats (Cyfip1 +/- ) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1 +/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1 +/- 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 Cyfip1 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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