title: Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice.
abstract: Autism is a complex neurodevelopmental disorder with high heritability. grik2 (which encodes the GluK2 subunit of kainate receptors) has been identified as a susceptibility gene in Autism Spectrum Disorders (ASD), but its role in the core and associated symptoms of ASD still remains elusive. We used mice lacking GluK2 (GluK2 KO) to examine their endophenotype with a view to modeling aspects of autism, including social deficits, stereotyped and repetitive behavior and decreased cognitive abilities. Anxiety was recorded in the elevated plus maze, social behavior in a three-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task. In addition, GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behavior and showed no memory. However, GluK2 KO mice were impaired in spatial reversal learning. These behavioral data together with previously published electrophysiology showing severe anomalies in CA3 network activity, suggest a computational shift in this network for enhanced propensity of pattern completion that would explain the loss of behavioral flexibility in GluK2 KO mice. Although a single mutation cannot recapitulate the entire core symptoms of ASD, our data provide evidence for glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD.
authors.affiliation: Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Université de Bordeaux, CNRS, UMR 5287, 33 405, Talence, Cedex, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Micheau
authors.forename: Alice
authors.initials: A
authors.lastname: Vimeney
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Normand
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001321:Autistic Disorder / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D018782:Maze Learning / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D012193:Reversal Learning / Q000502:physiology*; D012919:Social Behavior; D013997:Time Factors; D000097806:GluK2 Kainate Receptor
chemical_list: D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor
keywords: GluK2 KO mice; autism spectrum disorder; behavioral flexibility; pattern separation/completion; social behavior; spatial learning; water maze