title: NMDA receptor-deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities.
abstract: N-methyl-d-aspartate (NMDA) receptor-deficient mice can be used to understand the role that NMDA receptors (NMDARs) play in the pathophysiology of neurodevelopmental disorders such as schizophrenia. Genetically modified mice with low levels of NR1 subunit (NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity and stereotypy at 3, 6 and 12 weeks of age in NR1 knockdown mice and their wild-type littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested 4 weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Milenkovic
authors.forename: C A
authors.initials: CA
authors.lastname: Mielnik
authors.forename: A J
authors.initials: AJ
authors.lastname: Ramsey
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D056344:Executive Function / Q000502:physiology; D005260:Female; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000502:physiology
chemical_list: C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Cognition; GluN1; Grin1; executive function; locomotor activity; mouse; neurodevelopmental disorder; schizophrenia; social behaviour; stereotypy; working memory