Figure 1.

Synaptic signaling pathways associated with autism spectrum disorder (ASD). Alterations in the mechanistic target of rapamycin complex (mTOR) are considered risk factors for ASD. mTOR is activated by Rheb‐GTP. Upstream of Rheb is the tuberous sclerosis complex (TSC1–TSC2). TSC2 contains a GTPase‐activating protein (GAP) domain that converts Rheb from GTP‐bound form to its inactive GDP‐bound form. Several upstream signaling pathways ranging from PI3K–AKT, Ras–ERK, LKB1–AMPK and Wnt–GSK3β pathways, positively or negatively regulate mTOR signaling. (AMPK, AMP‐activated protein kinase; ERK, extracellular signal‐regulated kinase; GSK3β, glycogen synthase kinase 3β; and PI3K, phosphoinositide 3‐kinase). The mTOR pathway is also regulated by the brain‐derived neurotrophic factor (BDNF) which binds to the tropomyosin‐related kinase B (TRKB). BDNF plays a key role in the development and the plasticity of the central nervous system and it is considered a risk factor for ASD because increased levels of BDNF concentration have been observed in the serum and brain of patients with ASD. PI3K is also regulated by the synaptic protein SHANK, which is associated with metabotropic glutamate receptors type 1 (mGluR1) via the neuronal scaffolding protein HOMER1. The mTOR complex is a key modulator of protein synthesis by direct phosphorylation of 4E‐binding proteins (4E‐BPs) and activation of the ribosomal subunit S6 kinase (S6Ks), which in turn phosphorylate translation initiation factors. Thus, mTOR blocks the activation of cell autophagy and promotes cell proliferation, growth, and differentiation. The activity of the proteasome is also regulated by neuronal activity. The expression of UBE3A is increased through the transcription factor MEF2 and regulates the degradation of ARC protein, which promotes the internalization of AMPA‐R and regulates excitatory synapse development. Variations in the neuronal L‐type Ca²⁺ channel α subunit CACNA1C have been associated with Timothy syndrome and with ASD. In addition, Ca²⁺/calmodulin‐dependent protein kinases are associated with components of the neuronal complex including the fragile X mental retardation protein (FMRP) and its protein interaction CYFIP1, which also consider candidate genes in ASD. UBE3A: ubiquitin–protein ligase E3A; MEF2: myocyte‐specific enhancer factor 2; ARC: activity‐regulated cytoskeleton‐associated protein; AMPR: AMPA receptors; CYFIP1: cytoplasmic FMRP‐interacting protein 1