The role of nitric oxide in brain disorders: Autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders

Abstract

Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differentiation and proliferation of neurons. It also regulates synaptic activity, plasticity and vesicle trafficking. NO affects cellular signalling through protein S-nitrosylation, the NO-mediated posttranslational modification of cysteine thiols (SNO). SNO can affect protein activity, protein-protein interaction and protein localization. Numerous studies have shown that excessive NO and SNO can lead to nitrosative stress in the nervous system, contributing to neuropathology. In this review, we summarize the role of NO and SNO in the progression of neurodevelopmental, psychiatric and neurodegenerative disorders, with special attention to autism spectrum disorder (ASD). We provide mechanistic insights into the contribution of NO in diverse brain disorders. Finally, we suggest that pharmacological agents that can inhibit or augment the production of NO as well as new approaches to modulate the formation of SNO-proteins can serve as a promising approach for the treatment of diverse brain disorders.

Keywords: Alzheimer's disease; Autism spectrum disorder; Brain disorders; Neurodegeneration; Neurodevelopmental disorders; Nitric oxide; Psychiatry; S-nitrosylation; SHANK3.

Fig. 1

Schematic representation of NO signalling pathways in physiological conditions. Ca⁺² influx activates nNOS by binding with calmodulin, leading to NO production. NO activates soluble guanylate cyclase to produce cGMP which interacts with many intracellular proteins such as PKG. PKG leads to CREB phosphorylation which leads into transcriptional activation of different genes. NO, directly and indirectly, leads to S-nitrosylation (SNO) of many proteins and receptors. SNO modification of proteins can alter the receptor activity, protein-protein interaction and protein localization leading to alteration in signalling. Increased level of NO increases nitrosative stress, proxynitrite formation, tyrosine nitration of proteins, which ultimately may lead into cell death.

Fig. 2

NO signalling in autism spectrum disorder (ASD). Schematic representation of NO involvement in ASD. Mutation in SHANK3 gene may cause imbalance in Ca⁺² homeostasis. Ca⁺² is responsible for intracellular NO production which leads to S-nitrosylation of many proteins. S-nitrosylation of calcineurin inhibited its phosphatase activity which leads to increased levels of phosphorylated (P) synapsin-1 and CREB. P-synapsin-1 increases vesicle mobilization and P-CREB increases the recruitment of transcriptional co-activators and cortical activity. S-nitrosylation of syntaxin1a, inhibited its binding with Munc-18 which ultimately leads to increased vesicle docking and fusion.

Fig. 3

NO signalling in Alzheimer's disease (AD). Schematic representation of the involvement of NO in AD progression. Altered Ca⁺² influx leads into aberrant NO production in cells, which S-nitrosylates many proteins and increases nitrosative stress, peroxynitrite formation, protein tyrosine nitration, which alters the signalling pathways and lead into cell death in AD. SNO of parkin and XIAP alter their E3 ubiquitin ligase activity. SNO of PDI disrupts its chaperone activity which enhances the accumulation of misfolded proteins in cells. SNO of Cdk and DRP-1 alters the mitochondrial dynamics.

Fig. 4

The involvement of NO in brain disorders. Alterations in NO and other NO-related molecular changes in the different brain disorders are presented. Abbreviations: NO: nitric oxide; Ntyr: nitrotyrosine; GSNO: S-Nitrosoglutathione; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase.