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

doi:10.1016/j.biopsych.2015.01.017

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 journal › Article › Academic › peer-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 language	English
Pages (from-to)	485-495
Number of pages	11
Journal	Biological Psychiatry
Volume	78
Issue number	7
DOIs	https://doi.org/10.1016/j.biopsych.2015.01.017
Publication status	Published - 1-Oct-2015
Externally published	Yes

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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10.1016/j.biopsych.2015.01.017

Cite this

Bruining, H., Matsui, A., Oguro-Ando, A., Kahn, R. S., van't Spijker, H. M., Akkermans, G., Stiedl, O., van Engeland, H., Koopmans, B., van Lith, H. A., Oppelaar, H., Tieland, L., Nonkes, L. J., Yagi, T., Kaneko, R., Burbach, J. P. H., Yamamoto, N., & Kas, M. J. (2015). Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development. Biological Psychiatry, 78(7), 485-495. https://doi.org/10.1016/j.biopsych.2015.01.017

Bruining, Hilgo ; Matsui, Asuka ; Oguro-Ando, Asami ; Kahn, Rene S. ; van't Spijker, Heleen M. ; Akkermans, Guus ; Stiedl, Oliver ; van Engeland, Herman ; Koopmans, Bastijn ; van Lith, Hein A. ; Oppelaar, Hugo ; Tieland, Liselotte ; Nonkes, Lourens J. ; Yagi, Takeshi ; Kaneko, Ryosuke ; Burbach, J. Peter H. ; Yamamoto, Nobuhiko ; Kas, Martien J. / Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development. In: Biological Psychiatry. 2015 ; Vol. 78, No. 7. pp. 485-495.

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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.",

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",

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

year = "2015",

month = oct,

day = "1",

doi = "10.1016/j.biopsych.2015.01.017",

language = "English",

volume = "78",

pages = "485--495",

journal = "Biological Psychiatry",

issn = "1873-2402",

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number = "7",

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Bruining, H, Matsui, A, Oguro-Ando, A, Kahn, RS, van't Spijker, HM, Akkermans, G, Stiedl, O, van Engeland, H, Koopmans, B, van Lith, HA, Oppelaar, H, Tieland, L, Nonkes, LJ, Yagi, T, Kaneko, R, Burbach, JPH, Yamamoto, N & Kas, MJ 2015, 'Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development', Biological Psychiatry, vol. 78, no. 7, pp. 485-495. https://doi.org/10.1016/j.biopsych.2015.01.017

Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development. / Bruining, Hilgo; Matsui, Asuka; Oguro-Ando, Asami; Kahn, Rene S.; van't Spijker, Heleen M.; Akkermans, Guus; Stiedl, Oliver; van Engeland, Herman; Koopmans, Bastijn; van Lith, Hein A.; Oppelaar, Hugo; Tieland, Liselotte; Nonkes, Lourens J.; Yagi, Takeshi; Kaneko, Ryosuke; Burbach, J. Peter H.; Yamamoto, Nobuhiko; Kas, Martien J.

In: Biological Psychiatry, Vol. 78, No. 7, 01.10.2015, p. 485-495.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development

AU - Bruining, Hilgo

AU - Matsui, Asuka

AU - Oguro-Ando, Asami

AU - Kahn, Rene S.

AU - van't Spijker, Heleen M.

AU - Akkermans, Guus

AU - Stiedl, Oliver

AU - van Engeland, Herman

AU - Koopmans, Bastijn

AU - van Lith, Hein A.

AU - Oppelaar, Hugo

AU - Tieland, Liselotte

AU - Nonkes, Lourens J.

AU - Yagi, Takeshi

AU - Kaneko, Ryosuke

AU - Burbach, J. Peter H.

AU - Yamamoto, Nobuhiko

AU - Kas, Martien J.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - Associative learning

KW - Autism spectrum disorder

KW - Genetic mapping

KW - Information processing

KW - Pcdh9

KW - QTL

KW - Quantitative trait locus

KW - Recognition

KW - Sensory cortex

KW - Social cognition

KW - CHROMOSOME SUBSTITUTION STRAINS

KW - AUTISM SPECTRUM DISORDER

KW - CONDITIONED CONTEXTUAL FEAR

KW - NON-CLUSTERED PROTOCADHERIN

KW - DELTA-PROTOCADHERINS

KW - DISCRIMINATION PROCEDURE

KW - INTERMEDIATE PHENOTYPES

KW - PSYCHIATRIC-DISORDERS

KW - NERVOUS-SYSTEM

KW - ANIMAL-MODELS

U2 - 10.1016/j.biopsych.2015.01.017

DO - 10.1016/j.biopsych.2015.01.017

M3 - Article

VL - 78

SP - 485

EP - 495

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 1873-2402

IS - 7

ER -