title: Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.
abstract: Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/-heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/-knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/-and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/-mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/-mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/-mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability.
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Benevento
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Oomen
authors.affiliation: Synome Ltd., Babraham Research Campus, Cambridge CB22 3AT, UK.|Department of Psychology, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Alexa E
authors.initials: AE
authors.lastname: Horner
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.|Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: Houshang
authors.initials: H
authors.lastname: Amiri
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Tessa
authors.initials: T
authors.lastname: Jacobs
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pauwels
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Frega
authors.affiliation: Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Synome Ltd., Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Maksym V
authors.initials: MV
authors.lastname: Kopanitsa
authors.affiliation: Centre for Clinical Brain Sciences, Chancellors Building, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.affiliation: Department of Cell Biology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Catharina E E M
authors.initials: CE
authors.lastname: Van der Zee
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.|Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Glennon
authors.affiliation: Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.|Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.
authors.forename: Nael Nadif
authors.initials: NN
authors.lastname: Kasri
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000503:physiopathology; D057895:Haploinsufficiency / Q000235:genetics / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D007858:Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation
chemical_list: C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase