title: Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.
abstract: The brain-specific Ras/Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG(+/-)), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG(+/-) mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG(+/-) mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG(+/-) mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG(+/-) mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.
authors.affiliation: Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology, Schwerzenbach, Switzerland.
authors.forename: Mary
authors.initials: M
authors.lastname: Muhia
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.forename: Foivos
authors.initials: F
authors.lastname: Markopoulos
authors.forename: Irene
authors.initials: I
authors.lastname: Knuesel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009483:Neuropsychological Tests; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins