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Background <p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component, and over a thousand associated genes have been identified, including <i>CNTNAP2</i> and <i>SHANK3</i>. Our previous work using <i>Cntnap2</i><sup>-/-</sup> and <i>Shank3</i><sup>Δ4–22</sup> ASD mouse models implicated dysregulated nitric oxide (NO) signaling in ASD-related behaviors, which were improved by inhibition of neuronal nitric oxide synthase (nNOS) with 7-Nitroindazole (7-NI). However, the molecular mechanisms linking NO signaling to ASD pathology remain poorly defined.</p> Methods <p>We performed mass spectrometry-based global proteomic profiling of cortical tissue from both mouse models under baseline conditions and following 7-NI treatment. Systems biology and bioinformatics analyses were used to identify differentially expressed proteins, enriched pathways, and treatment-responsive networks. Cross-model comparisons were performed to assess molecular convergence and overlap with human ASD-risk genes. Behavioral and biochemical assessments were reanalyzed to evaluate ASD-like phenotypes and treatment effects.</p> Results <p>Treatment with 7-NI improved ASD-like behavioral deficits in <i>Cntnap2</i> and <i>Shank3</i> mutant mice, including increased sociability and reduced anxiety-like behavior. 7-NI was also associated with attenuation of cortical protein alterations across synaptic, neuronal, and metabolic pathways, shifting subsets of dysregulated proteins toward wild-type expression levels. Despite distinct genetic mutations, the two models converged at the protein and pathway levels, including treatment-responsive proteins encoded by high-confidence human ASD risk genes.</p> Limitations <p>Analyses were restricted to cortical tissue; additional brain regions may reveal complementary mechanisms. Mass spectrometry may underrepresent low-abundance proteins; larger sample sizes could improve statistical power. Potential off-target effects of 7-NI should also be considered.</p> Conclusions <p>These findings show that nNOS inhibition improves ASD-like behaviors and is associated with partial normalization of altered cortical proteins across two genetically distinct ASD mouse models that display convergent molecular changes, including proteins encoded by high-confidence ASD risk genes.</p>

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Nitric oxide inhibition ameliorates cortical proteomic changes in the Cntnap2-/- and Shank3Δ4–22 mouse models of autism spectrum disorder

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Wisam Bazbaz,
  • Maryam Kartawy,
  • Igor Khaliulin,
  • Haitham Amal

摘要

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component, and over a thousand associated genes have been identified, including CNTNAP2 and SHANK3. Our previous work using Cntnap2-/- and Shank3Δ4–22 ASD mouse models implicated dysregulated nitric oxide (NO) signaling in ASD-related behaviors, which were improved by inhibition of neuronal nitric oxide synthase (nNOS) with 7-Nitroindazole (7-NI). However, the molecular mechanisms linking NO signaling to ASD pathology remain poorly defined.

Methods

We performed mass spectrometry-based global proteomic profiling of cortical tissue from both mouse models under baseline conditions and following 7-NI treatment. Systems biology and bioinformatics analyses were used to identify differentially expressed proteins, enriched pathways, and treatment-responsive networks. Cross-model comparisons were performed to assess molecular convergence and overlap with human ASD-risk genes. Behavioral and biochemical assessments were reanalyzed to evaluate ASD-like phenotypes and treatment effects.

Results

Treatment with 7-NI improved ASD-like behavioral deficits in Cntnap2 and Shank3 mutant mice, including increased sociability and reduced anxiety-like behavior. 7-NI was also associated with attenuation of cortical protein alterations across synaptic, neuronal, and metabolic pathways, shifting subsets of dysregulated proteins toward wild-type expression levels. Despite distinct genetic mutations, the two models converged at the protein and pathway levels, including treatment-responsive proteins encoded by high-confidence human ASD risk genes.

Limitations

Analyses were restricted to cortical tissue; additional brain regions may reveal complementary mechanisms. Mass spectrometry may underrepresent low-abundance proteins; larger sample sizes could improve statistical power. Potential off-target effects of 7-NI should also be considered.

Conclusions

These findings show that nNOS inhibition improves ASD-like behaviors and is associated with partial normalization of altered cortical proteins across two genetically distinct ASD mouse models that display convergent molecular changes, including proteins encoded by high-confidence ASD risk genes.