Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome

被引：54

作者：

Balemans, Monique C. M. ^{[1
,2
]}

Kasri, Nael Nadif ^{[3
]}

Kopanitsa, Maksym V. ^{[5
]}

Afinowi, Nurudeen O. ^{[5
]}

Ramakers, Ger ^{[6
]}

Peters, Theo A. ^{[4
]}

Beynon, Andy J. ^{[4
]}

Janssen, Sanne M. ^{[1
]}

van Summeren, Rik C. J. ^{[1
,2
]}

Eeftens, Jorine M. ^{[1
]}

Eikelenboom, Nathalie ^{[1
]}

Benevento, Marco ^{[3
]}

Tachibana, Makoto ^{[7
]}

Shinkai, Yoichi ^{[7
]}

Kleefstra, Tjitske ^{[1
]}

van Bokhoven, Hans ^{[1
,3
]}

Van der Zee, Catharina E. E. M. ^{[2
]}

机构：

[1] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Cell Biol, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Otorhinolaryngol, Donders Inst Brain, NL-6500 HB Nijmegen, Netherlands

[5] Synome Ltd, Cambridge CB22 3AT, England

[6] Univ Amsterdam, Dept Dev Psychol, NL-1018 WB Amsterdam, Netherlands

[7] Kyoto Univ, Inst Virus Res, Sakyo Ku, Expt Res Ctr Infect Dis, Kyoto 606, Japan

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 05期

关键词：

MENTAL-RETARDATION PROTEIN; SUBTELOMERIC DELETION SYNDROME; HISTONE METHYLTRANSFERASES; DIFFERENTIAL CONTRIBUTION; SYNAPTIC PLASTICITY; RECOGNITION MEMORY; PREFRONTAL CORTEX; FEAR EXTINCTION; ANIMAL-MODEL; AMYGDALA;

D O I：

10.1093/hmg/dds490

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(/)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(/) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(/) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(/) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(/) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.

引用

页码：852 / 866

页数：15

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