Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Sci Rep. 2017 Jan 10:7:40284. doi: 10.1038/srep40284.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Chromosome Deletion
  • Chromosomes, Human, Pair 9 / genetics
  • Cognition Disorders / genetics*
  • Cognition Disorders / physiopathology
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / physiopathology
  • Haploinsufficiency / genetics
  • Haploinsufficiency / physiology
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Hippocampus / physiopathology
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Learning / physiology*
  • Memory / physiology
  • Mice
  • Mice, Knockout
  • Mutation

Substances

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

Supplementary concepts

  • Kleefstra Syndrome