Genetic and environmental contributions to autism spectrum disorder through mechanistic target of rapamycin

Abstract

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual’s reciprocal social interaction and communication ability. Numerous genetic and environmental conditions are associated with ASD, including tuberous sclerosis complex (TSC), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome, fragile X syndrome (FXS), and neurofibromatosis 1 (NF1). The pathogenic molecular mechanisms of these diseases are integrated into the hyperactivation of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Rodent models of these diseases have shown high mTORC1 activity in the brain and ASD-related behavioral deficits, which were reversed by the mTORC1 inhibitor rapamycin. Environmental stress can also affect this signaling pathway. In utero exposure to valproate caused ASD in offspring and enhanced mTORC1 activity in the brain, which was sensitive to mTORC1 inhibition. mTORC1 is a signaling hub for diverse cellular functions, including protein synthesis, through the phosphorylation of its targets, such as ribosomal protein S6 kinases. Metabotropic glutamate receptor 5-mediated synaptic function is also affected by the dysregulation of mTORC1 activity, such as in FXS and TSC. Reversing these downstream changes that are associated with mTORC1 activation normalizes behavioral defects in rodents. Despite abundant preclinical evidence, few clinical studies have investigated the treatment of ASD and cognitive deficits. Therapeutics other than mTORC1 inhibitors failed to show efficacy in FXS and NF1. mTORC1 inhibitors have been tested mainly in TSC, and their effects on ASD and neuropsychological deficits are promising. mTORC1 is a promising target for the pharmacological treatment of ASD associated with mTORC1 activation.