title: 15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes.
abstract: The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder and schizophrenia, though the clinical profile varies considerably. Two mouse models of this syndrome, with hemizygous deletion of the orthologous region in the murine genome, have recently been shown to recapitulate a number of the behavioral and physiological deficits that characterize the human condition. Still, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral and physiological deficits in mice than the 15q13.3 hemizygous deletion. Here we report the characterization of a 15q13.3 knockout mouse. We observed marked deficits including altered seizure susceptibility, autistic behavior-related phenotypes, and auditory sensory processing. Several of these deficits, albeit less pronounced, were also found in the 15q13.3 hemizygous littermates indicating a gene-dosage dependency. Our findings strongly indicate that studies of the hemi- and homozygous 15q13.3 mouse strains will facilitate understanding of the biological mechanisms of severe mental disorders.
authors.affiliation: Synaptic Transmission, In Vitro, Neuroscience Research DK, H. Lundbeck A/S, Valby, Denmark.|Institute of Biological Psychiatry, Mental Health Center, Sct. Hans, Mental Health Services, Roskilde, Denmark.|Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Forsingdal
authors.affiliation: Synaptic Transmission, In Vitro, Neuroscience Research DK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Fejgin
authors.affiliation: Synaptic Transmission, In Vitro, Neuroscience Research DK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: V
authors.initials: V
authors.lastname: Nielsen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Center, Sct. Hans, Mental Health Services, Roskilde, Denmark.|Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark.|iPSYCH, The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Werge
authors.affiliation: Synaptic Transmission, In Vitro, Neuroscience Research DK, H. Lundbeck A/S, Valby, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001308:Auditory Perceptual Disorders / Q000235:genetics / Q000503:physiopathology; D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D001522:Behavior, Animal; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003213:Conditioning, Psychological; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D005239:Fear; D057898:Hemizygote; D006720:Homozygote; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D051379:Mice; D018345:Mice, Knockout; D009425:Nesting Behavior; D010433:Pentylenetetrazole / Q000633:toxicity; D065808:Prepulse Inhibition; D013216:Reflex, Startle; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012640:Seizures / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D012919:Social Behavior; D014828:Vocalization, Animal
chemical_list: D003292:Convulsants; D010433:Pentylenetetrazole