PMID- 30621732
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20211204
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 12
IP  - 1
DP  - 2019 Jan 8
TI  - Effects of rapamycin on social interaction deficits and gene expression in mice 
      exposed to valproic acid in utero.
PG  - 3
LID - 10.1186/s13041-018-0423-2 [doi]
LID - 3
AB  - The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role 
      in cell metabolism, growth, and proliferation. The overactivation of mTOR has 
      been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), 
      such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor 
      rapamycin improved social interaction deficits in mouse models of TSC. Prenatal 
      exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that 
      are exposed to VPA in utero have been used as an animal model of ASD. Activation 
      of the mTOR signaling pathway was recently observed in rodents that were exposed 
      to VPA in utero, and rapamycin ameliorated social interaction deficits. The 
      present study investigated the effect of rapamycin on social interaction deficits 
      in both adolescence and adulthood, and gene expressions in mice that were exposed 
      to VPA in utero. We subcutaneously injected 600 mg/kg VPA in pregnant mice on 
      gestational day 12.5 and used the pups as a model of ASD. The pups were 
      intraperitoneally injected with rapamycin or an equal volume of vehicle once 
      daily for 2 consecutive days. The social interaction test was conducted in the 
      offspring after the last rapamycin administration at 5-6 weeks of ages 
      (adolescence) or 10-11 weeks of age (adulthood). Whole brains were collected 
      after the social interaction test in the adulthood, and microarray and Western 
      blot analyses were performed. Mice that were exposed to VPA and treated with 
      vehicle exhibited a decrease in social interaction compared with control mice 
      that were treated with vehicle. Rapamycin treatment in VPA-exposed mice improved 
      social deficits. Mice that were exposed to VPA and treated with vehicle exhibited 
      the aberrant expression of genes in the mTOR signaling pathway, and rapamycin 
      treatment recovered changes in the expression of some genes, including Fyb and 
      A330094K24Rik. Rapamycin treatment suppressed S6 phosphorylation in VPA-exposed 
      mice. Aberrant gene expression was associated with social interaction deficits in 
      VPA-exposed mice. Rapamycin may be an effective treatment for non-syndromic ASD 
      in adolescent and adult patients who present impairments in the mTOR signaling 
      pathway.
FAU - Kotajima-Murakami, Hiroko
AU  - Kotajima-Murakami H
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
AD  - Department of Biosciences, School of Science and Engineering, Teikyo University, 
      1-1 Toyosatodai, Utsunomiya-shi, Tochigi, Japan.
FAU - Kobayashi, Toshiyuki
AU  - Kobayashi T
AD  - Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo 
      University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan.
FAU - Kashii, Hirofumi
AU  - Kashii H
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
AD  - Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 
      7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
FAU - Sato, Atsushi
AU  - Sato A
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
AD  - Department of Pediatrics, The University of Tokyo Hospital, 7-3-1 Hongo, 
      Bunkyo-ku, Tokyo, Japan.
FAU - Hagino, Yoko
AU  - Hagino Y
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
FAU - Tanaka, Miho
AU  - Tanaka M
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
AD  - Department of Developmental Disorders, National Institute of Mental Health, 
      National Center of Neurology and Psychiatry, 4-1-1 Higashimachi, Kodaira-shi, 
      Tokyo, Japan.
FAU - Nishito, Yasumasa
AU  - Nishito Y
AD  - Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical 
      Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
FAU - Takamatsu, Yukio
AU  - Takamatsu Y
AD  - Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical 
      Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
FAU - Uchino, Shigeo
AU  - Uchino S
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.
AD  - Department of Biosciences, School of Science and Engineering, Teikyo University, 
      1-1 Toyosatodai, Utsunomiya-shi, Tochigi, Japan.
FAU - Ikeda, Kazutaka
AU  - Ikeda K
AD  - Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 
      2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan. ikeda-kz@igakuken.or.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190108
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - 0 (Ribosomal Protein S6)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Body Weight/drug effects
MH  - Female
MH  - Gene Expression Regulation, Developmental/*drug effects
MH  - Gene Regulatory Networks/drug effects
MH  - *Interpersonal Relations
MH  - Mice, Inbred C57BL
MH  - Motor Activity/drug effects
MH  - Phosphorylation/drug effects
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/*genetics/physiopathology
MH  - Ribosomal Protein S6/genetics/metabolism
MH  - Signal Transduction/drug effects/genetics
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Valproic Acid/*adverse effects
PMC - PMC6325753
OTO - NOTNLM
OT  - Autism spectrum disorder
OT  - Rapamycin
OT  - Valproic acid
OT  - mTOR signaling pathway
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All of the animal experiments were 
      performed in accordance with the Guidelines for the Care of Laboratory Animals of 
      the Tokyo Metropolitan Institute of Medical Science, and the housing conditions 
      were approved by the Institutional Animal Care and Use Committee. CONSENT FOR 
      PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they 
      have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral 
      with regard to jurisdictional claims in published maps and institutional 
      affiliations.
EDAT- 2019/01/10 06:00
MHDA- 2019/06/14 06:00
PMCR- 2019/01/08
CRDT- 2019/01/10 06:00
PHST- 2018/09/30 00:00 [received]
PHST- 2018/12/25 00:00 [accepted]
PHST- 2019/01/10 06:00 [entrez]
PHST- 2019/01/10 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2019/01/08 00:00 [pmc-release]
AID - 10.1186/s13041-018-0423-2 [pii]
AID - 423 [pii]
AID - 10.1186/s13041-018-0423-2 [doi]
PST - epublish
SO  - Mol Brain. 2019 Jan 8;12(1):3. doi: 10.1186/s13041-018-0423-2.