title: Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.
abstract: Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ellegood
authors.affiliation: Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Anagnostou
authors.affiliation: Laboratory of Behavioral Neurosciences, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Babineau
authors.affiliation: 1] Laboratory of Behavioral Neurosciences, National Institute of Mental Health, Bethesda, MD, USA [2] Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Crawley
authors.affiliation: Department of Neurosciences and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Neurosciences and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Genestine
authors.affiliation: Department of Neurosciences and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: DiCicco-Bloom
authors.affiliation: The Brain-Body Institute, McMaster University, Hamilton, ON, Canada.
authors.forename: J K Y
authors.initials: JK
authors.lastname: Lai
authors.affiliation: The Brain-Body Institute, McMaster University, Hamilton, ON, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Foster
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Peñagarikano
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: L K
authors.initials: LK
authors.lastname: Pacey
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: D R
authors.initials: DR
authors.lastname: Hampson
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: C L
authors.initials: CL
authors.lastname: Laliberté
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Mills
authors.affiliation: Departments of Medicine and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Tam
authors.affiliation: Departments of Medicine and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: L R
authors.initials: LR
authors.lastname: Osborne
authors.affiliation: Departments of Neurology and Neurotherapeutics, Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kouser
authors.affiliation: Departments of Neurology and Neurotherapeutics, Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Espinosa-Becerra
authors.affiliation: Departments of Neurology and Neurotherapeutics, Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Departments of Neurology and Neurotherapeutics, Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Powell
authors.affiliation: Child Psychiatry Branch, National Institutes of Mental Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Raznahan
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Robins
authors.affiliation: Department of Mental Biology, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nakai
authors.affiliation: Department of Mental Biology, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakatani
authors.affiliation: Department of Mental Biology, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takumi
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: M C
authors.initials: MC
authors.lastname: van Eede
authors.affiliation: Department of Pharmacology, Vanderbilt Kennedy Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Kerr
authors.affiliation: Department of Pharmacology, Vanderbilt Kennedy Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Muller
authors.affiliation: Department of Pharmacology, Vanderbilt Kennedy Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Blakely
authors.affiliation: Department of Pharmacology, Vanderbilt Kennedy Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Veenstra-VanderWeele
authors.affiliation: 1] Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Henkelman
authors.affiliation: 1] Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lerch
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D005810:Multigene Family / Q000235:genetics*