PMID- 26027949 OWN - NLM STAT- MEDLINE DCOM- 20160524 LR - 20211203 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 97 DP - 2015 Oct TI - mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits. PG - 220-32 LID - S0028-3908(15)00165-3 [pii] LID - 10.1016/j.neuropharm.2015.04.035 [doi] AB - Autism spectrum disorder (ASD) is multifactorial, with both genetic as well as environmental factors working in concert to develop the autistic phenotype. Immunological disturbances in autistic individuals have been reported and a role for food allergy has been suggested in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well. Therefore, the mTOR pathway may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD. In this study it was investigated whether the mTOR pathway plays a role in food allergy-induced behavioral and immunological deficits. Mice were orally sensitized and challenged with whey protein. Meanwhile, cow's milk allergic (CMA) mice received daily treatment of rapamycin. The validity of the CMA model was confirmed by showing increased allergic immune responses. CMA mice showed reduced social interaction and increased repetitive self-grooming behavior. Enhanced mTORC1 activity was found in the brain and ileum of CMA mice. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of CMA mice. This effect was associated with increase of Treg associated transcription factors in the ileum of CMA mice. These findings indicate that mTOR activation may be central to both the intestinal, immunological, and psychiatric ASD-like symptoms seen in CMA mice. It remains to be investigated whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms. CI - Copyright (c) 2015 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Wu, Jiangbo AU - Wu J AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. FAU - de Theije, Caroline G M AU - de Theije CG AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. FAU - da Silva, Sofia Lopes AU - da Silva SL AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands. FAU - van der Horst, Hilma AU - van der Horst H AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. FAU - Reinders, Margot T M AU - Reinders MT AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. FAU - Broersen, Laus M AU - Broersen LM AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands. FAU - Willemsen, Linette E M AU - Willemsen LE AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. FAU - Kas, Martien J H AU - Kas MJ AD - Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Garssen, Johan AU - Garssen J AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands. FAU - Kraneveld, Aletta D AU - Kraneveld AD AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. Electronic address: a.d.kraneveld@uu.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150529 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Immunosuppressive Agents) RN - 0 (Multiprotein Complexes) RN - 0 (RNA, Messenger) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Brain/drug effects/metabolism MH - Cattle MH - Chemokine CCL2/blood MH - Compulsive Behavior/drug therapy/physiopathology MH - Diet MH - Disease Models, Animal MH - Grooming/drug effects/physiology MH - Ileum/drug effects/metabolism MH - Immunosuppressive Agents/pharmacology MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice, Inbred C3H MH - Milk Hypersensitivity/drug therapy/*physiopathology/psychology MH - Multiprotein Complexes/metabolism MH - RNA, Messenger/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/pharmacology MH - Social Behavior MH - T-Lymphocytes, Regulatory/drug effects/physiology MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - Autism spectrum disorder (ASD) OT - Cow's milk allergy (CMA) OT - Mammalian target of rapamycin (mTOR) OT - Rapamycin OT - Regulatory T (Treg) cells EDAT- 2015/06/02 06:00 MHDA- 2016/05/25 06:00 CRDT- 2015/06/02 06:00 PHST- 2014/11/19 00:00 [received] PHST- 2015/04/05 00:00 [revised] PHST- 2015/04/30 00:00 [accepted] PHST- 2015/06/02 06:00 [entrez] PHST- 2015/06/02 06:00 [pubmed] PHST- 2016/05/25 06:00 [medline] AID - S0028-3908(15)00165-3 [pii] AID - 10.1016/j.neuropharm.2015.04.035 [doi] PST - ppublish SO - Neuropharmacology. 2015 Oct;97:220-32. doi: 10.1016/j.neuropharm.2015.04.035. Epub 2015 May 29.