Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice.
The 9q34.3 subtelomeric deletion syndrome is a newly defined mental retardation syndrome, caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene. Patients also have childhood hypotonia, facial dysmorphisms, delay in reaching developmental milestones, and behavioral problems like aggressive outbursts, hypoactivity, or autistic-like features. Male and female heterozygous Ehmt1 knockout mice (Ehmt1(+/-), aged 1-20 months, kept on a C57BL/6J background), were used to investigate whether they mimic the patients behavioral characteristics by comparing their behavior to wildtype littermates. The Ehmt1(+/-) mice revealed reduced activity and exploration, with increased anxiety compared to wildtype mice when exposed to novel environments in the open field, object exploration, marble burying, light-dark box, mirrored chamber and T-maze tests. They also demonstrated diminished social play when encountering a mouse from a different litter, and a delayed or absent response to social novelty when exposed to a stranger mouse. However, no differences in phenotyper home cage locomotor activity or rotarod motor function were observed between Ehmt1(+/-) and wildtype mice. Together, these results indicate that the hypoactivity and the autistic-like features of 9q34.3 subtelomeric deletion syndrome patients are recapitulated in this Ehmt1(+/-) mouse model, and that the hypoactivity is apparently not caused by any motor dysfunction. Together, these observations make it plausible that the Ehmt1(+/-) mouse is a faithful mammalian model for the autistic-like behavioral features of patients with the 9q34.3 subtelomeric deletion syndrome.
Balemans
Monique C M
MC
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. m.balemans@antrg.umcn.nl
Huibers
Manon M H
MM
Eikelenboom
Nathalie W D
NW
Kuipers
Arthur J
AJ
van Summeren
Rik C J
RC
Pijpers
Michael M C A
MM
Tachibana
Makoto
M
Shinkai
Yoichi
Y
van Bokhoven
Hans
H
Van der Zee
Catharina E E M
CE
D000221:Adaptation, Ocular / Q000502:physiology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000209:etiology*; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics*; D001835:Body Weight / Q000235:genetics; D004195:Disease Models, Animal; D022041:Euchromatin / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D005838:Genotype; D006120:Grooming / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency*; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D012737:Sex Factors; D012919:Social Behavior
D022041:Euchromatin; D011495:Histone-Lysine N-Methyltransferase