title: Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader-Willi syndrome.
abstract: The genes in the imprinted cluster on human chromosome 15q11-q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader-Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over-eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction. To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS-IC(+/-)) and the five-choice serial reaction time task (5-CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open-field behaviour and sensorimotor gating were also assessed. PWS-IC(+/-) mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5-CSRTT, the PWS-IC(+/-) mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention. Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11-q13 to behavioural and cognitive function generally.
authors.affiliation: Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Dinko
authors.initials: D
authors.lastname: Relkovic
authors.forename: Christine M
authors.initials: CM
authors.lastname: Doe
authors.forename: Trevor
authors.initials: T
authors.lastname: Humby
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnstone
authors.forename: James L
authors.initials: JL
authors.lastname: Resnick
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Holland
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Wilkinson
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Isles
mesh_terms: D000818:Animals; D001288:Attention; D001835:Body Weight; D001921:Brain / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004192:Discrimination, Psychological; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005183:Failure to Thrive / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics* / Q000502:physiology; D009483:Neuropsychological Tests; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D011930:Reaction Time; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion