title: Euchromatin histone methyltransferase 1 regulates cortical neuronal network development.
abstract: Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.
authors: Department of Neuroinformatics, Radboud University Nijmegen, Faculty of Science, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Marijn Bart
authors: MB
authors: Martens
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Monica
authors: M
authors: Frega
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Jessica
authors: J
authors: Classen
authors: Department of Neuroinformatics, Radboud University Nijmegen, Faculty of Science, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands.
authors: Lisa
authors: L
authors: Epping
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Elske
authors: E
authors: Bijvank
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Marco
authors: M
authors: Benevento
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Human Genetics, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Hans
authors: H
authors: van Bokhoven
authors: Department of Neuroinformatics, Radboud University Nijmegen, Faculty of Science, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Paul
authors: P
authors: Tiesinga
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Dirk
authors: D
authors: Schubert
authors: Donders Institute for Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.|Department of Human Genetics, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors: Nael
authors: N
authors: Nadif Kasri
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000254:growth & development / Q000503:physiopathology; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000201:enzymology* / Q000254:growth & development* / Q000503:physiopathology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats
chemical_list: C455847:EHMT1 protein, human; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase