Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.
Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.
Nakatani
Jin
J
Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Tamada
Kota
K
Hatanaka
Fumiyuki
F
Ise
Satoko
S
Ohta
Hisashi
H
Inoue
Kiyoshi
K
Tomonaga
Shozo
S
Watanabe
Yasuhito
Y
Chung
Yeun Jun
YJ
Banerjee
Ruby
R
Iwamoto
Kazuya
K
Kato
Tadafumi
T
Okazawa
Makoto
M
Yamauchi
Kenta
K
Tanda
Koichi
K
Takao
Keizo
K
Miyakawa
Tsuyoshi
T
Bradley
Allan
A
Takumi
Toru
T
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D001522:Behavior, Animal; D002884:Chromosomes, Human, Pair 15; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D045442:Rotarod Performance Test; D015398:Signal Transduction
D044405:Receptor, Serotonin, 5-HT2C