Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development

Hilgo Bruining, Asuka Matsui, Asami Oguro-Ando, Rene S. Kahn, Heleen M. van't Spijker, Guus Akkermans, Oliver Stiedl, Herman van Engeland, Bastijn Koopmans, Hein A. van Lith, Hugo Oppelaar, Liselotte Tieland, Lourens J. Nonkes, Takeshi Yagi, Ryosuke Kaneko, J. Peter H. Burbach, Nobuhiko Yamamoto, Martien J. Kas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)485-495
Number of pages11
JournalBiological Psychiatry
Volume78
Issue number7
DOIs
Publication statusPublished - 1-Oct-2015
Externally publishedYes

Keywords

  • Associative learning
  • Autism spectrum disorder
  • Genetic mapping
  • Information processing
  • Pcdh9
  • QTL
  • Quantitative trait locus
  • Recognition
  • Sensory cortex
  • Social cognition
  • CHROMOSOME SUBSTITUTION STRAINS
  • AUTISM SPECTRUM DISORDER
  • CONDITIONED CONTEXTUAL FEAR
  • NON-CLUSTERED PROTOCADHERIN
  • DELTA-PROTOCADHERINS
  • DISCRIMINATION PROCEDURE
  • INTERMEDIATE PHENOTYPES
  • PSYCHIATRIC-DISORDERS
  • NERVOUS-SYSTEM
  • ANIMAL-MODELS

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