Mark Alan Fitzgerald

Background:  Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication, along with repetitive behaviors, that affects approximately 1 in 36 children in the United States.¹ Neuroinflammation has been proposed as one of the drivers of ASD pathogenesis.^1,2 In the prefrontal cortex, upregulation of immune and inflammatory pathways alongside downregulation of myelination and synapse control genes disrupts the neural circuits underlying social motivation and emotional regulation.² Many of these ASD-implicated pathways are regulated by microRNAs (miRNAs).^1-3 MiRNAs are short, non-coding RNA molecules of approximately 18–24 nucleotides that regulate gene expression post-transcriptionally and play critical roles in neurodevelopment. Importantly, miRNAs can be packaged within exosomes and measured noninvasively in extracellular biofluids such as saliva, making them attractive biomarker candidates.⁴ Despite the prevalence of ASD, there are no current biomarkers in use due to the condition’s complex etiology.⁴

Research Objective:  This review investigated how dysregulated miRNAs play a role in neuroinflammation found in ASD pathogenesis and how that role can be used to create biomarkers for early diagnosis.

Search Methods:  A PubMed database search was conducted for results from 2019-2026 using the following keywords: “autism”, “neuroinflammation”, “miRNA”, and “gene regulation.”

Results:  In a valproic acid-induced rat model of ASD, plasma exosomal miR-30b-5p was significantly downregulated in plasma exosomes and in the brain relative to controls. The authors found elevated levels of inflammatory cytokines, including IL-6, IL-1β, and TNF-α, in both the blood and brains of the ASD rat models.¹ MiR-30b-5p was found to suppress neuroinflammation by targeting epidermal growth factor receptor (EGFR) and downregulating downstream MAPK signaling pathways.¹ Intracerebroventricular delivery of miR-30b-5p agomir (exogenous delivery vehicle) reduced pro-inflammatory cytokines IL-6, TNF-α, and IL-1β and ameliorated ASD-like behaviors.¹ In a separate cross-sectional case-control study of 443 children aged 2–6, salivary miRNA profiling identified a panel of 4 miRNAs that distinguished children with ASD from those with typical development.⁴ Logistic regression analysis incorporating this panel achieved a sensitivity of 89.2% and a specificity of 32%, with overall diagnostic accuracy comparable to currently used subjective ASD screening tools such as the MCHAT-R.⁴ The test’s sensitivity minimizes false negatives, an important characteristic for screening tools. Bioinformatic target analysis further confirmed that the differentially expressed miRNAs regulate neurodevelopmental genes implicated in ASD pathogenesis.⁴

Conclusions:  These findings support the role of miRNA dysregulation, particularly miR-30b-5p, in the neuroinflammatory processes associated with ASD. In addition, salivary miRNA profiles show potential as objective tools for early ASD screening and diagnosis. Further research in human populations is needed to determine whether plasma exosomal miR-30b-5p can improve the accuracy and reliability of future biomarker panels for ASD.

Works Cited

1. Zheng Z, Wu Q, Zhang X. Plasma exosomal miR-30b-5p attenuates neuroinflammation in a rat model of autism spectrum disorder. Front Psychiatry. 2025;16. doi:3389/fpsyt.2025.1630782
2. Mooney C, Parlante A, Canarutto G, et al. Deregulated mRNA and microRNA Expression Patterns in the Prefrontal Cortex of the BTBR Mouse Model of Autism. Mol Neurobiol. 2025;62(8):10614-10634. doi:1007/s12035-025-04900-x
3. Garrido-Torres N, Guzmán-Torres K, García-Cerro S, et al. miRNAs as biomarkers of autism spectrum disorder: a systematic review and meta-analysis. European child & adolescent psychiatry. 2024;33(9):2957-2990. doi:1007/s00787-023-02138-3
4. Hicks SD, Carpenter RL, Wagner KE, et al. Saliva MicroRNA Differentiates Children With Autism From Peers With Typical and Atypical Development. J Am Acad Child Adolesc Psychiatry. 2020;59(2):296-308. doi:1016/j.jaac.2019.03.017