The NO Answer for Autism Spectrum Disorder

Abstract

Autism spectrum disorders (ASDs) include a wide range of neurodevelopmental disorders. Several reports showed that mutations in different high-risk ASD genes lead to ASD. However, the underlying molecular mechanisms have not been deciphered. Recently, they reported a dramatic increase in nitric oxide (NO) levels in ASD mouse models. Here, they conducted a multidisciplinary study to investigate the role of NO in ASD. High levels of nitrosative stress biomarkers are found in both the Shank3 and Cntnap2 ASD mouse models. Pharmacological intervention with a neuronal NO synthase (nNOS) inhibitor in both models led to a reversal of the molecular, synaptic, and behavioral ASD-associated phenotypes. Importantly, treating iPSC-derived cortical neurons from patients with SHANK3 mutation with the nNOS inhibitor showed similar therapeutic effects. Clinically, they found a significant increase in nitrosative stress biomarkers in the plasma of low-functioning ASD patients. Bioinformatics of the SNO-proteome revealed that the complement system is enriched in ASD. This novel work reveals, for the first time, that NO plays a significant role in ASD. Their important findings will open novel directions to examine NO in diverse mutations on the spectrum as well as in other neurodevelopmental disorders. Finally, it suggests a novel strategy for effectively treating ASD.

Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons

“…iPSC-based models offer an alternative to understanding the effect of genomic mutations and associations on neural cells 6,16,21,[43][44][45][46][47][48] . The majority of studies investigated NPCs and neurons derived from ASD patient-specific iPSC in vitro and only a few havestudied the role of glial cells from ASD patients using iPSC technology.…”

Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation

“…Recently, interesting studies have put in light connections between the specific genetic mutation of the Shank3 gene occurring in autism, a condition associated with deficits in communication and social skills, and excessive NO synthesis, which is responsible for aberrant protein nitrosation and S-nitrosylation [ 64 , 65 , 66 , 67 ]. Elevated levels of different SNO proteins functionally involved in the synaptic vesicle cycle, neurotransmission, and glutamatergic pathway, such as protein phosphatase catalytic subunit α-Ppp3ca, syntaxin-1a, vesicle-associated membrane protein 3, and others, were found in Shank3 KO mouse models [ 66 , 67 ]. Collectively, these observations provide insights into the specific pathological role of dysregulated NO production in autism spectrum disorders.…”

“…Moreover, this compound is able to slow down the progressive neurodegeneration in a Parkinson’s disease in vivo model [ 87 ]. Very recently, 7-NI was also used to demonstrate the pathological role of NO in autism development, and the in vivo administration of this compound to a Shank3 mouse (M1) model of autism disease led to the recovery of a normal behavioral phenotype [ 67 ].…”

Age and Gender-Dependent in Nitric Oxide Postnatal Change Activity in the Rat Brain

“…In the brain, endogenous NO acts as a diffusible neurotransmitter mainly produced by nNOS, activated upon glutamate binding to postsynaptic N-methyl-Daspartate (NMDA) receptors (Chachlaki and Prevot, 2020;Fernando et al, 2022). Since Nnos has been identified at different time points in various cell types of the central nervous system (CNS) (Maccallini and Amoroso, 2023), in certain areas of the brain, it is only temporarily expressed (Chung et al, 2004;Imura et al, 2005) and there is a gradual increase in others (Tripathi et al, 2023) during embryonic and postnatal development. Additionally, during the first month of postnatal life, histochemical and immunocytochemical research have characterized the distribution of NO-producing neurons in the rat corpus callosum structure (cc) (Barbaresi et al, 2020).…”