Hilgo Bruining1, Asuka Matsui2, Asami Oguro-Ando3, René S Kahn4, Heleen M Van't Spijker3, Guus Akkermans3, Oliver Stiedl5, Herman van Engeland4, Bastijn Koopmans6, Hein A van Lith7, Hugo Oppelaar3, Liselotte Tieland3, Lourens J Nonkes3, Takeshi Yagi8, Ryosuke Kaneko8, J Peter H Burbach3, Nobuhiko Yamamoto2, Martien J Kas3. 1. 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. 2. Neuroscience Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. 3. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. 6. Sylics (Synaptologics BV), Amsterdam, The Netherlands. 7. 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. 8. KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
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.
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: Amila Zuko; Asami Oguro-Ando; Roland van Dijk; Sara Gregorio-Jordan; Bert van der Zwaag; J Peter H Burbach Journal: Cell Adh Migr Date: 2016-03-03 Impact factor: 3.405
Authors: Remco T Molenhuis; Hilgo Bruining; Myrna J V Brandt; Petra E van Soldt; Hanifa J Abu-Toamih Atamni; J Peter H Burbach; Fuad A Iraqi; Richard F Mott; Martien J H Kas Journal: Mol Autism Date: 2018-12-13 Impact factor: 7.509
Authors: Remco T Molenhuis; Hilgo Bruining; Esther Remmelink; Leonie de Visser; Maarten Loos; J Peter H Burbach; Martien J H Kas Journal: J Neurodev Disord Date: 2016-03-02 Impact factor: 4.025
Authors: Emily M A Lewis; Kesavan Meganathan; Dustin Baldridge; Paul Gontarz; Bo Zhang; Azad Bonni; John N Constantino; Kristen L Kroll Journal: Mol Autism Date: 2019-12-30 Impact factor: 7.509