title: Dietary interventions that reduce mTOR activity rescue autistic-like behavioral deficits in mice.
abstract: Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T+Itpr3tf/J mice. Cow's milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Caroline G M
authors.initials: CGM
authors.lastname: de Theije
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Sofia Lopes
authors.initials: SL
authors.lastname: da Silva
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Abbring
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Hilma
authors.initials: H
authors.lastname: van der Horst
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Laus M
authors.initials: LM
authors.lastname: Broersen
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Linette
authors.initials: L
authors.lastname: Willemsen
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
authors.forename: Martien
authors.initials: M
authors.lastname: Kas
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands. Electronic address: a.d.kraneveld@uu.nl.
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000178:diet therapy*; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000187:drug effects; D019587:Dietary Supplements; D005512:Food Hypersensitivity / Q000523:psychology; D006120:Grooming; D006639:Histidine / Q000627:therapeutic use; D007073:Immunoglobulin E / Q000276:immunology; D007398:Interpersonal Relations; D007421:Intestine, Small / Q000378:metabolism; D008239:Lysine / Q000627:therapeutic use; D008297:Male; D008407:Mast Cells; D051379:Mice; D016269:Milk Hypersensitivity / Q000523:psychology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000627:therapeutic use
chemical_list: D013912:Threonine; D007073:Immunoglobulin E; D006639:Histidine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D008239:Lysine
keywords: Amino acids; Autism spectrum disorder (ASD); Cow’s milk allergy (CMA); Gut-brain axis; Mammalian target of rapamycin (mTOR)