mTOR, a Potential Target to Treat Autism Spectrum Disorder

Abstract

Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.

Fig. (1)

Signaling pathway involving mTORC1. Various stimuli converge on mTORC1 pathway via a number of routes. mTORC1 activation impacts on different cellular physiology, such as protein synthesis, cap-dependent mRNA translation, and autophagy. Here mutations in TSC1/2, PTEN, FMR1, and NF1 cause constitutive mTORC1 activation and syndromic ASD. Akt, protein kinase B; eIF4E, eukaryotic initiation factor 4E; ERK, extracellular signal-regulated kinase; 4E-BP, 4E-binding protein; FMRP, fragile X mental retardation protein; GSK3, glycogen synthase kinase 3; IR, insulin receptor; MAP2K, mitogen-activated protein kinase kinase; mGluR, metabotropic glutamate receptor; mTOR, mammalian target of rapamycin; NF1, neurofibromin; NMDAR, NMDA receptor; PDK, phosphoinositide-dependent kinase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma; Rheb, Ras homolog enriched in brain; RYK, receptor-like tyrosine kinase; S6K, p70 ribosomal S6 kinase; TSC, tuberous sclerosis complex; ULK1, unc51-like kinase 1.