title: Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome.
abstract: Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Monique C M
authors.initials: MC
authors.lastname: Balemans
authors.forename: Nael Nadif
authors.initials: NN
authors.lastname: Kasri
authors.forename: Maksym V
authors.initials: MV
authors.lastname: Kopanitsa
authors.forename: Nurudeen O
authors.initials: NO
authors.lastname: Afinowi
authors.forename: Ger
authors.initials: G
authors.lastname: Ramakers
authors.forename: Theo A
authors.initials: TA
authors.lastname: Peters
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Beynon
authors.forename: Sanne M
authors.initials: SM
authors.lastname: Janssen
authors.forename: Rik C J
authors.initials: RC
authors.lastname: van Summeren
authors.forename: Jorine M
authors.initials: JM
authors.lastname: Eeftens
authors.forename: Nathalie
authors.initials: N
authors.lastname: Eikelenboom
authors.forename: Marco
authors.initials: M
authors.lastname: Benevento
authors.forename: Makoto
authors.initials: M
authors.lastname: Tachibana
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shinkai
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Catharina E E M
authors.initials: CE
authors.lastname: Van der Zee
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004195:Disease Models, Animal; D006330:Heart Defects, Congenital / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D017966:Pyramidal Cells / Q000473:pathology; D013569:Synapses / Q000473:pathology
chemical_list: C455847:EHMT1 protein, human; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase