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

Authors
  • Shofty, Ben1
  • Bergmann, Eyal2
  • Zur, Gil2
  • Asleh, Jad2
  • Bosak, Noam2
  • Kavushansky, Alexandra2
  • Castellanos, F Xavier3
  • Ben-Sira, Liat4
  • Packer, Roger J5
  • Vezina, Gilbert L6
  • Constantini, Shlomi4
  • Acosta, Maria T7
  • Kahn, Itamar8
  • 1 Department of Neuroscience, Rappaport Faculty of Medicine and Institute, Technion - Israel Institute of Technology, Haifa, Israel; The Gilbert Israeli NF Center, Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, and Tel Aviv University, Tel Aviv, Israel. , (Israel)
  • 2 Department of Neuroscience, Rappaport Faculty of Medicine and Institute, Technion - Israel Institute of Technology, Haifa, Israel. , (Israel)
  • 3 Department of Child and Adolescent Psychiatry, Hassenfeld Children's Hospital at NYU Langone, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • 4 The Gilbert Israeli NF Center, Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel Aviv Medical Center, and Tel Aviv University, Tel Aviv, Israel. , (Israel)
  • 5 The Gilbert Family Neurofibromatosis Institute, Children's National Health System, Department of Neurology and Pediatrics, George Washington University, Washington, DC, USA.
  • 6 Department of Diagnostic Imaging and Radiology, Children's National Health System, Washington, DC, USA.
  • 7 The Gilbert Family Neurofibromatosis Institute, Children's National Health System, Department of Neurology and Pediatrics, George Washington University, Washington, DC, USA; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA.
  • 8 Department of Neuroscience, Rappaport Faculty of Medicine and Institute, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address: [email protected] , (Israel)
Type
Published Article
Journal
Neurobiology of Disease
Publisher
Elsevier
Publication Date
Oct 01, 2019
Volume
130
Pages
104479–104479
Identifiers
DOI: 10.1016/j.nbd.2019.104479
PMID: 31128207
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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