Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse

NEUROBIOLOGY OF DISEASE

卷:130

Article

Shofty, Ben^1,2,3  Bergmann, Eyal¹  Zur, Gil¹  Asleh, Jad¹  Bosak, Noam¹  Kavushansky, Alexandra¹  Castellanos, F. Xavier^4,5  Ben-Sira, Liat^2,3  Packer, Roger J.⁶  Vezina, Gilbert L.⁷  Constantini, Shlomi^2,3  Acosta, Maria T.^6,8  Kahn, Itamar¹ 

[1] Technion Israel Inst Technol, Rappaport Fac Med & Inst, Dept Neurosci, Haifa, Israel

[2] Dana Childrens Hosp, Tel Aviv Med Ctr, Dept Pediat Neurosurg, Gilbert Israeli NF Ctr, Tel Aviv, Israel

[3] Tel Aviv Univ, Tel Aviv, Israel

[4] NYU Langone, Hassenfeld Childrens Hosp, Dept Child & Adolescent Psychiat, New York, NY USA

[5] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA

[6] George Washington Univ, Dept Neurol & Pediat, Childrens Natl Hlth Syst, Gilbert Family Neurofibromatosis Inst, Washington, DC USA

[7] Childrens Natl Hlth Syst, Dept Diagnost Imaging & Radiol, Washington, DC USA

[8] NHGRI, NIH, Bethesda, MD 20892 USA

关键词: Neurofibromatosis type 1;    Autism;    ADHD;    fMRI;    Mouse model;    Pediatric patients;   

DOI  :  10.1016/j.nbd.2019.104479

来源: Elsevier

【 摘 要 】

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1(+/-)). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1(+/-) mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1(+/-) mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

【 授权许可】

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