Neuroimmunomodulation of autistic-like behavior: targeting mTOR via dietary interventions

Abstract

Autism spectrum disorder (ASD) is characterized by impairments in social behavior and communication and the presence of repetitive and stereotyped behavior. The etiology of ASD is thought to be related to an interaction of the complex genetic basis with environmental contributions. Immunological disturbances, in particular food allergic reactions, have been suggested to be involved in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway result in enhanced mTOR signaling in the brain in various mouse models of ASD and are associated with the development of ASD phenotypes. In addition, the mTOR signaling pathway is involved in directing immune responses towards allergy. Therefore, the mTOR signaling pathway may be the therapeutic target for the treatment of food allergy-associated ASD. In this thesis it is shown that cow’s milk allergic mice displayed reduced social interaction and enhanced repetitive self-grooming behavior. In addition, it is also demonstrated that the mTOR signaling was enhanced in the prefrontal cortex and amygdala and distal ileum of allergic mice. The specific mTOR inhibitor rapamycin improved the behavioral impairments of allergic mice. Moreover, rapamycin inhibited the humoral immune responses and mucosal mast cell activation in cow’s milk allergic mice. These results suggest that the mTOR signaling pathway is centrally involved in immunological, neurological, and behavioral changes in cow’s milk allergic mice. Based on in vitro studies with allergic mast cells, we designed a specific mTOR-inhibiting amino acid diet containing increased relative amount of histidine, threonine, lysine and reduced relative amount of leucine, isoleucine, valine. Dietary intervention with the mTOR targeting amino acid diet improved social interaction and normalized repetitive self-grooming behavior of cow’s milk allergic mice. This effect was associated with inhibition of the mTOR signaling in the prefrontal cortex and amygdala of allergic mice. Furthermore, dietary intervention with a multi-nutrient supplementation diet containing anti-inflammatory and neuroprotective ingredients improved the behavioral impairments and inhibited the mTOR signaling in the prefrontal cortex and amygdala of allergic mice. In a genetic mouse model for autistic-like behavior, dietary intervention with the mTOR targeting amino acid diet normalized the repetitive self-grooming behavior and inhibited the mTOR signaling in the prefrontal cortex and somatosensory cortex, while the multi-nutrient supplementation diet had no effect on behavioral deficits and the mTOR signaling pathway in the brain. These findings suggest that the mTOR targeting amino acid diet may directly inhibit the mTOR signaling in the brain, rather than via suppressing the allergic immune responses, and thereby improve the brain functions and behavioral impairments in mice.