title: Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.
abstract: BACKGROUND
  Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development.
  
  
  METHODS
  Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology.
  
  
  RESULTS
  Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed.
  
  
  CONCLUSIONS
  This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes.
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: h.bruining@umcutrecht.nl.
authors: Hilgo
authors: H
authors: Bruining
authors: Neuroscience Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors: Asuka
authors: A
authors: Matsui
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Asami
authors: A
authors: Oguro-Ando
authors: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: René S
authors: RS
authors: Kahn
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Heleen M
authors: HM
authors: Van't Spijker
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Guus
authors: G
authors: Akkermans
authors: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam.
authors: Oliver
authors: O
authors: Stiedl
authors: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Herman
authors: H
authors: van Engeland
authors: Sylics (Synaptologics BV), Amsterdam, The Netherlands.
authors: Bastijn
authors: B
authors: Koopmans
authors: Division of Animal Welfare & Laboratory Animal Science, Department of Animals in Science and Society, Program Emotion and Cognition, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
authors: Hein A
authors: HA
authors: van Lith
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Hugo
authors: H
authors: Oppelaar
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Liselotte
authors: L
authors: Tieland
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Lourens J
authors: LJ
authors: Nonkes
authors: KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors: Takeshi
authors: T
authors: Yagi
authors: KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors: Ryosuke
authors: R
authors: Kaneko
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J Peter H
authors: JP
authors: Burbach
authors: Neuroscience Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors: Nobuhiko
authors: N
authors: Yamamoto
authors: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Martien J
authors: MJ
authors: Kas
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology; D002874:Chromosome Mapping; D003071:Cognition / Q000502:physiology; D003712:Dendrites / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D040641:Quantitative Trait Loci; D021641:Recognition, Psychology / Q000502:physiology*; D066191:Sensorimotor Cortex / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D055139:Sensory Gating / Q000235:genetics / Q000502:physiology*; D012938:Social Perception
keywords: Associative learning; Autism spectrum disorder; Genetic mapping; Information processing; Pcdh9; QTL; Quantitative trait locus; Recognition; Sensory cortex; Social cognition