Cargando…

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

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(+/−)...

Descripción completa

Detalles Bibliográficos
Autores principales: Benevento, Marco, Oomen, Charlotte A., Horner, Alexa E., Amiri, Houshang, Jacobs, Tessa, Pauwels, Charlotte, Frega, Monica, Kleefstra, Tjitske, Kopanitsa, Maksym V., Grant, Seth G. N., Bussey, Timothy J., Saksida, Lisa M., Van der Zee, Catharina E.E.M., van Bokhoven, Hans, Glennon, Jeffrey C., Kasri, Nael Nadif
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223204/
https://www.ncbi.nlm.nih.gov/pubmed/28071689
http://dx.doi.org/10.1038/srep40284
_version_ 1782493132238094336
author Benevento, Marco
Oomen, Charlotte A.
Horner, Alexa E.
Amiri, Houshang
Jacobs, Tessa
Pauwels, Charlotte
Frega, Monica
Kleefstra, Tjitske
Kopanitsa, Maksym V.
Grant, Seth G. N.
Bussey, Timothy J.
Saksida, Lisa M.
Van der Zee, Catharina E.E.M.
van Bokhoven, Hans
Glennon, Jeffrey C.
Kasri, Nael Nadif
author_facet Benevento, Marco
Oomen, Charlotte A.
Horner, Alexa E.
Amiri, Houshang
Jacobs, Tessa
Pauwels, Charlotte
Frega, Monica
Kleefstra, Tjitske
Kopanitsa, Maksym V.
Grant, Seth G. N.
Bussey, Timothy J.
Saksida, Lisa M.
Van der Zee, Catharina E.E.M.
van Bokhoven, Hans
Glennon, Jeffrey C.
Kasri, Nael Nadif
author_sort Benevento, Marco
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5223204
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-52232042017-01-17 Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation Benevento, Marco Oomen, Charlotte A. Horner, Alexa E. Amiri, Houshang Jacobs, Tessa Pauwels, Charlotte Frega, Monica Kleefstra, Tjitske Kopanitsa, Maksym V. Grant, Seth G. N. Bussey, Timothy J. Saksida, Lisa M. Van der Zee, Catharina E.E.M. van Bokhoven, Hans Glennon, Jeffrey C. Kasri, Nael Nadif Sci Rep Article 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. Nature Publishing Group 2017-01-10 /pmc/articles/PMC5223204/ /pubmed/28071689 http://dx.doi.org/10.1038/srep40284 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Benevento, Marco
Oomen, Charlotte A.
Horner, Alexa E.
Amiri, Houshang
Jacobs, Tessa
Pauwels, Charlotte
Frega, Monica
Kleefstra, Tjitske
Kopanitsa, Maksym V.
Grant, Seth G. N.
Bussey, Timothy J.
Saksida, Lisa M.
Van der Zee, Catharina E.E.M.
van Bokhoven, Hans
Glennon, Jeffrey C.
Kasri, Nael Nadif
Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title_full Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title_fullStr Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title_full_unstemmed Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title_short Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation
title_sort haploinsufficiency of ehmt1 improves pattern separation and increases hippocampal cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223204/
https://www.ncbi.nlm.nih.gov/pubmed/28071689
http://dx.doi.org/10.1038/srep40284
work_keys_str_mv AT beneventomarco haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT oomencharlottea haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT horneralexae haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT amirihoushang haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT jacobstessa haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT pauwelscharlotte haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT fregamonica haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT kleefstratjitske haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT kopanitsamaksymv haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT grantsethgn haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT busseytimothyj haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT saksidalisam haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT vanderzeecatharinaeem haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT vanbokhovenhans haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT glennonjeffreyc haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation
AT kasrinaelnadif haploinsufficiencyofehmt1improvespatternseparationandincreaseshippocampalcellproliferation