title: Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism.
abstract: Restricted repetitive behaviors are core symptoms of autism spectrum disorders (ASDs). The range of symptoms encompassed by the repetitive behavior domain includes lower-order stereotypy and self-injury, and higher-order indices of circumscribed interests and cognitive rigidity. Heterogeneity in clinical ASD profiles suggests that specific manifestations of repetitive behavior reflect differential neuropathology. The present studies utilized a set of phenotyping tasks to determine a repetitive behavior profile for the C58/J mouse strain, a model of ASD core symptoms. In an observational screen, C58/J demonstrated overt motor stereotypy, but not over-grooming, a commonly-used measure for mouse repetitive behavior. Amphetamine did not exacerbate motor stereotypy, but had enhanced stimulant effects on locomotion and rearing in C58/J, compared to C57BL/6J. Both C58/J and Grin1 knockdown mice, another model of ASD-like behavior, had marked deficits in marble-burying. In a nose poke task for higher-order repetitive behavior, C58/J had reduced holeboard exploration and preference for non-social, versus social, olfactory stimuli, but did not demonstrate cognitive rigidity following familiarization to an appetitive stimulus. Analysis of available high-density genotype data indicated specific regions of divergence between C58/J and two highly-sociable strains with common genetic lineage. Strain genome comparisons identified autism candidate genes, including Cntnap2 and Slc6a4, located within regions divergent in C58/J. However, Grin1, Nlgn1, Sapap3, and Slitrk5, genes linked to repetitive over-grooming, were not in regions of divergence. These studies suggest that specific repetitive phenotypes can be used to distinguish ASD mouse models, with implications for divergent underlying mechanisms for different repetitive behavior profiles.
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: ssmoy@med.unc.edu.
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Moy
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Natallia V
authors.initials: NV
authors.lastname: Riddick
authors.affiliation: Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Viktoriya D
authors.initials: VD
authors.lastname: Nikolova
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Chemical Biology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Teng
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Agster
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Nonneman
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Young
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Lorinda K
authors.initials: LK
authors.lastname: Baker
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Nadler
authors.affiliation: Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Bodfish
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012903:Smell / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D000661:Amphetamine
keywords: Autism spectrum disorder; Circumscribed interests; Hyperactivity; NMDA receptor; Olfaction; SNP analysis