Euchromatin histone methyltransferase 1 regulates cortical neuronal network development

Sci Rep. 2016 Oct 21:6:35756. doi: 10.1038/srep35756.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / physiopathology
  • Chromosome Deletion
  • Chromosomes, Human, Pair 9 / genetics
  • Craniofacial Abnormalities / genetics
  • Craniofacial Abnormalities / pathology
  • Craniofacial Abnormalities / physiopathology
  • Excitatory Postsynaptic Potentials
  • Haploinsufficiency
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Heart Defects, Congenital / physiopathology
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology*
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Intellectual Disability / physiopathology
  • Mice
  • Mice, Knockout
  • Nerve Net / enzymology*
  • Nerve Net / growth & development*
  • Nerve Net / physiopathology
  • Neurogenesis / genetics
  • Neurogenesis / physiology
  • Patch-Clamp Techniques
  • Rats

Substances

  • EHMT1 protein, human
  • GLP protein, mouse
  • Histone-Lysine N-Methyltransferase

Supplementary concepts

  • Kleefstra Syndrome