A cross-talk between nitric oxide and the glutamatergic system in a Shank3 mouse model of autism
Abstract
Nitric oxide (NO) is a multifunctional signaling molecule that plays a crucial role in synaptic transmission and neuronal function. Pioneering studies show that nitric oxide (NO) and S-nitrosylation (SNO, the NO-mediated posttranslational modification) can engender nitrosative stress in the brain, contributing to neurodegenerative diseases. Little is known, however, about the aberrant NO signaling in neurodevelopmental disorders including autism spectrum disorder (ASD). We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive NO levels and aberrant protein SNO. The glutamatergic system is involved in ASD, specifically in SHANK3 pathology. We used SNOTRAP technology to identify the SNO-proteome in the brain of the Shank3 mutant mice to understand the role of SNO in the glutamatergic system during the development of these mice. We conducted a systems biology analysis of the SNO-proteome to investigate the biological processes and signaling pathways in the brain of juvenile and adult Shank3 mutant and wild-type mice. The Shank3 mutation caused significant SNO-enrichment of a glutamate signaling pathway in the juvenile and adult mutant mice, although different protein subsets were S-nitrosylated in both ages. Cellular compartments analysis showed that "glutamatergic Synapse" is SNO-enriched significantly in the mutant mice of both ages. We also found eight S-nitrosylated proteins involved in glutamate transmission in both ages. 38 SNO-p…
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In non-syndromic ASD, SHANK3 mutations primarily manifest as direct disruptions to synaptic architecture and function without consistent extra-neurological anomalies.
“In non-syndromic ASD, SHANK3 mutations primarily manifest as direct disruptions to synaptic architecture and function without consistent extra-neurological anomalies (Hamoudi et al., 2022; Belenska-Todorova et al., 2025).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Hamoudi et al., 2022
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Qing, Z., Yin, Z., Chen, B., Rao, Z., Yin, D., Li, D., Lu, Y., Shi, M., Li, S., Xu, Y., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1964684
“In non-syndromic ASD, SHANK3 mutations primarily manifest as direct disruptions to synaptic architecture and function without consistent extra-neurological anomalies (Hamoudi et al., 2022; Belenska-Todorova et al., 2025).”
- Authors
- Hamoudi, W., Tripathi, M. K., Ojha, S. K., & Amal, H.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Amal, Haitham
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 188
- Pages
- 83-91
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W4282963547
- Cited by
- 34
- References
- 9
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 9 · 2023: 6
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- nitric oxide, S-nitrosylation, SHANK3, autism spectrum disorder, glutamatergic system, glutamate signaling, NMDA receptor NR1, neuronal nitric oxide synthase, neurodevelopmental disorders, synapses
- MeSH terms
- Autism Spectrum Disorder, Animals, Autistic Disorder, Disease Models, Animal, Microfilament Proteins, Nerve Tissue Proteins, Nitric Oxide, Glutamic Acid, Proteome, Mice
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