Early Neurobehavioral Characterization of the CD Mouse Model of Williams–Beuren Syndrome

Williams–Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.

[1]  M. Memo,et al.  Long-term behavioral effects of prenatal stress in the Fmr1-knock-out mouse model for fragile X syndrome , 2022, Frontiers in Cellular Neuroscience.

[2]  C. M. Davenport,et al.  Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice , 2022, Cell.

[3]  S. Pietropaolo,et al.  Ultrasonic Vocalizations in Adult C57BL/6J Mice: The Role of Sex Differences and Repeated Testing , 2022, Frontiers in behavioral neuroscience.

[4]  Wim E. Crusio,et al.  Autistic-like behavioral effects of prenatal stress in juvenile Fmr1 mice: the relevance of sex differences and gene–environment interactions , 2022, Scientific Reports.

[5]  E. Eyras,et al.  Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome , 2021, bioRxiv.

[6]  G. Marsicano,et al.  Communication and social interaction in the cannabinoid‐type 1 receptor null mouse: Implications for autism spectrum disorder , 2021, Autism research : official journal of the International Society for Autism Research.

[7]  V. Campuzano,et al.  Chlorzoxazone, A BKCa Channel Agonist, Rescues The Pathological Phenotypes Of Williams-Beuren Syndrome In A Preclinical Model , 2020, bioRxiv.

[8]  L. Ricceri,et al.  Ultrasonic vocalizations as a fundamental tool for early and adult behavioral phenotyping of Autism Spectrum Disorder rodent models , 2020, Neuroscience & Biobehavioral Reviews.

[9]  F. Bertapelli,et al.  Growth assessment in children with Williams-Beuren syndrome: a systematic review , 2020, Journal of Applied Genetics.

[10]  V. Campuzano,et al.  Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome , 2020, Scientific Reports.

[11]  Maria V. Sanchez-Vives,et al.  Altered Neocortical Dynamics in a Mouse Model of Williams–Beuren Syndrome , 2019, Molecular Neurobiology.

[12]  A. Beery,et al.  Inclusion of females does not increase variability in rodent research studies , 2018, Current Opinion in Behavioral Sciences.

[13]  L. Pérez-Jurado,et al.  Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model , 2018, PloS one.

[14]  M. Memo,et al.  Behavioral abnormalities in the Fmr1‐KO2 mouse model of fragile X syndrome: The relevance of early life phases , 2017, Autism research : official journal of the International Society for Autism Research.

[15]  Valérie Lemaire-Mayo,et al.  Age‐specific autistic‐like behaviors in heterozygous Fmr1‐KO female mice , 2017, Autism research : official journal of the International Society for Autism Research.

[16]  C. Mulle,et al.  Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome , 2016, Molecular Brain.

[17]  B. Kaang,et al.  Effects of the Female Estrous Cycle on the Sexual Behaviors and Ultrasonic Vocalizations of Male C57BL/6 and Autistic BTBR T+ tf/J Mice , 2016, Experimental neurobiology.

[18]  J. Clayton Studying both sexes: a guiding principle for biomedicine , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  L. Pérez-Jurado,et al.  Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams-Beuren Syndrome. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[20]  Wim E Crusio,et al.  Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome , 2015, Neuropsychopharmacology.

[21]  Y. Hérault,et al.  Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder. , 2014, Human molecular genetics.

[22]  Mark J. Harris,et al.  Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2 , 2013, Behavioural Brain Research.

[23]  L. Hurley,et al.  Female Presence and Estrous State Influence Mouse Ultrasonic Courtship Vocalizations , 2012, PloS one.

[24]  James Y. Zhang,et al.  Reduced Excitatory Neurotransmission and Mild Autism-Relevant Phenotypes in Adolescent Shank3 Null Mutant Mice , 2012, The Journal of Neuroscience.

[25]  Jacqueline N. Crawley,et al.  Communication Impairments in Mice Lacking Shank1: Reduced Levels of Ultrasonic Vocalizations and Scent Marking Behavior , 2011, PloS one.

[26]  J. N. Crawley,et al.  Unusual repertoire of vocalizations in adult BTBR T+tf/J mice during three types of social encounters , 2011, Genes, brain, and behavior.

[27]  E Alleva,et al.  Translating mouse vocalizations: prosody and frequency modulation 1 , 2011, Genes, brain, and behavior.

[28]  C. Mervis,et al.  Auditory function and hearing loss in children and adults with Williams syndrome: Cochlear impairment in individuals with otherwise normal hearing , 2010, American journal of medical genetics. Part C, Seminars in medical genetics.

[29]  B. Pober Williams-Beuren syndrome. , 2010, The New England journal of medicine.

[30]  C. Caligioni Assessing Reproductive Status/Stages in Mice , 2009, Current protocols in neuroscience.

[31]  M. Porter,et al.  Psychopathological and Behavior Impairments in Williams-Beuren Syndrome: The Influence of Gender, Chronological Age, and Cognition , 2009, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[32]  Maria Luisa Scattoni,et al.  Ultrasonic vocalizations: A tool for behavioural phenotyping of mouse models of neurodevelopmental disorders , 2009, Neuroscience & Biobehavioral Reviews.

[33]  C. Schubert The genomic basis of the Williams – Beuren syndrome , 2008, Cellular and Molecular Life Sciences.

[34]  Jacqueline N. Crawley,et al.  Unusual Repertoire of Vocalizations in the BTBR T+tf/J Mouse Model of Autism , 2008, PloS one.

[35]  Shiaoching Gong,et al.  Minimal aberrant behavioral phenotypes of neuroligin‐3 R451C knockin mice , 2008, Autism research : official journal of the International Society for Autism Research.

[36]  David C Reutens,et al.  Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. , 2008, Journal of child psychology and psychiatry, and allied disciplines.

[37]  A. Moles,et al.  Ultrasonic vocalizations emitted during dyadic interactions in female mice: A possible index of sociability? , 2007, Behavioural Brain Research.

[38]  Garet P. Lahvis,et al.  Affiliative Behavior, Ultrasonic Communication and Social Reward Are Influenced by Genetic Variation in Adolescent Mice , 2007, PloS one.

[39]  J. Crawley,et al.  Behavioral phenotyping of mouse models of neurodevelopmental disorders: Relevant social behavior patterns across the life span , 2007, Behavioural Brain Research.

[40]  B. Ryals,et al.  Sensorineural hearing loss in children and adults with Williams syndrome , 2005, American journal of medical genetics. Part A.

[41]  Brenda J Butka Imaging , 2003, JAMA.

[42]  C. Mervis Williams Syndrome: 15 Years of Psychological Research , 2003, Developmental neuropsychology.

[43]  L. Ricceri,et al.  Transgenic and knock‐out mouse pups: the growing need for behavioral analysis , 2002, Genes, brain, and behavior.

[44]  N. Masataka Why early linguistic milestones are delayed in children with Williams syndrome: late onset of hand banging as a possible rate–limiting constraint on the emergence of canonical babbling , 2001 .

[45]  G. Feng,et al.  Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP , 2000, Neuron.

[46]  L. Spear The adolescent brain and age-related behavioral manifestations , 2000, Neuroscience & Biobehavioral Reviews.

[47]  E. Alleva,et al.  A description of the ontogeny of mouse agonistic behavior. , 1998, Journal of comparative psychology.

[48]  E. Alleva,et al.  Ontogeny of amicable social behavior in the mouse: gender differences and ongoing isolation outcomes. , 1993, Developmental psychobiology.

[49]  A. Wessel,et al.  Statural growth in Williams-Beuren syndrome , 1992, European Journal of Pediatrics.

[50]  G Whitney,et al.  Ultrasonic vocalizing by adult female mice (Mus musculus). , 1985, Journal of comparative psychology.

[51]  Carla Gentile Matas,et al.  O perfil audiológico e a funcionalidade coclear na síndrome de Williams , 2022, CoDAS.

[52]  E. Alleva,et al.  Neonatal behaviors associated with ultrasonic vocalizations in mice (mus musculus): A slow-motion analysis. , 2004, Developmental psychobiology.