The role of nitric oxide in autism spectrum disorder: Towards novel strategies for treatment

Nitric oxide (NO) is a multifunctional signaling molecule that plays an important role in many physiological and pathophysiological processes including neuronal signaling. Pioneering works showed that NO can engender nitrosative stress in the nervous system, contributing to neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. In the case of autism spectrum disorder (ASD), there is no evidence for a link between NO and ASD. We hypothesized that Shank3 mutation leads to an imbalance of Ca+2 homeostasis leading to amplification of neuronal nitric oxide synthase (nNOS) activity and to NO-related molecular changes including SNO. SNO targets a wide range of prominent intracellular proteins leading to alteration in signaling pathways, which may be converged onto cellular and behavioral deficits. SNO-proteins in two ASD-related brain regions, cortex and striatum of young and adult InsG3680(+/+) mice, were identified by an innovative mass spectrometric method, SNOTRAP. We found changes of the SNO-proteome in the mutant compared to WT in both ages. Pathway analysis showed enrichment of processes affected in ASD. SNO-Calcineurin in mutant led to a significant increase of phosphorylated Synapsin1 and CREB, which affect synaptic vesicle mobilization and gene transcription, respectively. A significant increase of 3-nitrotyrosine was found in the cortical regions of the adult mutant, signaling both oxidative and nitrosative stress. This is the first study on NO-related molecular changes and SNO-signaling in the brain of an ASD mouse model that allows the characterization of key proteins, cellular pathways, and neurobiological mechanisms that might be targets for treatment in ASD.