Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Marco Benevento, Charlotte A. Oomen, Alexa E. Horner, Houshang Amiri, Tessa Jacobs, Charlotte Pauwels, Monica Frega, Tjitske Kleefstra, Maksym V. Kopanitsa, Seth G.N. Grant, Timothy J. Bussey, Lisa M. Saksida, Catharina E.E.M. Van Der Zee, Hans Van Bokhoven, Jeffrey C. Glennon, Nael Nadif Kasri

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    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.

    Original languageEnglish
    Article number40284
    JournalScientific reports
    Volume7
    DOIs
    Publication statusPublished - 10 Jan 2017

    Fingerprint

    Euchromatin
    Haploinsufficiency
    Cell Proliferation
    Aptitude
    Learning
    Knockout Mice
    Paired-Associate Learning
    Reversal Learning
    Sequence Deletion
    Dentate Gyrus
    Bromodeoxyuridine
    Intellectual Disability
    Fear
    Hippocampus
    Phenotype
    histone methyltransferase
    Genes
    Discrimination (Psychology)
    Proteins
    Kleefstra Syndrome

    Cite this

    Benevento, M., Oomen, C. A., Horner, A. E., Amiri, H., Jacobs, T., Pauwels, C., ... Kasri, N. N. (2017). Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation. Scientific reports, 7, [40284]. https://doi.org/10.1038/srep40284
    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. In: Scientific reports. 2017 ; Vol. 7.
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    title = "Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation",
    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.",
    author = "Marco Benevento and Oomen, {Charlotte A.} and Horner, {Alexa E.} and Houshang Amiri and Tessa Jacobs and Charlotte Pauwels and Monica Frega and Tjitske Kleefstra and Kopanitsa, {Maksym V.} and Grant, {Seth G.N.} and Bussey, {Timothy J.} and Saksida, {Lisa M.} and {Van Der Zee}, {Catharina E.E.M.} and {Van Bokhoven}, Hans and Glennon, {Jeffrey C.} and Kasri, {Nael Nadif}",
    year = "2017",
    month = "1",
    day = "10",
    doi = "10.1038/srep40284",
    language = "English",
    volume = "7",
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    Benevento, M, Oomen, CA, Horner, AE, Amiri, H, Jacobs, T, Pauwels, C, Frega, M, Kleefstra, T, Kopanitsa, MV, Grant, SGN, Bussey, TJ, Saksida, LM, Van Der Zee, CEEM, Van Bokhoven, H, Glennon, JC & Kasri, NN 2017, 'Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation' Scientific reports, vol. 7, 40284. https://doi.org/10.1038/srep40284

    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.

    In: Scientific reports, Vol. 7, 40284, 10.01.2017.

    Research output: Contribution to journalArticleAcademicpeer-review

    TY - JOUR

    T1 - Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

    AU - Benevento, Marco

    AU - Oomen, Charlotte A.

    AU - Horner, Alexa E.

    AU - Amiri, Houshang

    AU - Jacobs, Tessa

    AU - Pauwels, Charlotte

    AU - Frega, Monica

    AU - Kleefstra, Tjitske

    AU - Kopanitsa, Maksym V.

    AU - Grant, Seth G.N.

    AU - Bussey, Timothy J.

    AU - Saksida, Lisa M.

    AU - Van Der Zee, Catharina E.E.M.

    AU - Van Bokhoven, Hans

    AU - Glennon, Jeffrey C.

    AU - Kasri, Nael Nadif

    PY - 2017/1/10

    Y1 - 2017/1/10

    N2 - 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.

    AB - 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.

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