Erin Mikeska

Background: Conservative reports estimate Autism Spectrum Disorder (ASD) to affect 1 in 132 individuals which translates to around 52 million people globally. ¹ ASD is an umbrella term that by definition of the DSM-V includes symptoms of social impairment and repetitive behaviors.^1,2,3 The wide range of possible symptoms, the degree of manifestations of those symptoms, and the reality of limited access to healthcare for a large portion of the population all contribute to the difficulty in diagnosing and treating ASD and highlight the need for preventative measures. Numerous reports have connected maternal inflammation and increased cytokine activity, including interferon-γ (IFN-γ), with the diagnosis of ASD.^4,5 Research regarding IFN-γ suggests it plays a role in specific neurodevelopmental processes and that regulation of IFN-γ is, “critical to preventing pathological abnormalities during early neurogenesis and gliogenesis in several regions that are associated with cognitive performance and social behavior.”⁴ Despite this knowledge, the mechanisms by which environmental exposures, specifically infection, influence the development of ASD are still unknown. It is known that IFN-γ is a cytokine that mediates an inflammatory response through altering gene transcription of numerous other proteins.⁵ Specifically, IFN-γ binding to its receptor activates the JAK-STAT pathway which goes on to stimulate chromatin remodeling and alter gene transcription.⁶ Interestingly, there are IFN-γ receptors found on microglia, neurons, and astrocytes.⁶ Thus, it is plausible that the connection between IFN-γ and ASD lies in IFN-γ’s modulating role of gene transcription in the developing nervous system.

Objective(s): Investigating the mechanistic connection between the presence of interferon-gamma due to maternal immune activation and the manifestation of autism spectrum disorder in offspring. ^1,7,8

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following key words, “Autism Spectrum Disorder”, “Maternal Immune Activation”, “Interferon-gamma”, and “Folic Acid”

Results: As expected, the presence of IFN-γ in stem cells or initiation of Maternal Immune Activation (MIA) in mice resulted in abnormal neuronal growth patterns of the stem cells or mice offspring, respectively.^1,7,8 In taking this analysis a step further, when comparing the RNA transcriptomes of IFN-γ exposed offspring to the current database of gene expression for individuals with Autism Spectrum Disorder (ASD), the transcriptomic changes of the two datasets overlapped, suggesting that MIA may be a contributor to ASD.¹ More specifically, Maternal Immune Activation (MIA) in mice results in offspring genetic changes including downregulation of genes previously linked to behavior and learning.⁹ Examples of such genes include those of the GABA genes which ultimately effect functioning of GABAergic pathways.^1,10 Diving deeper into this mechanism, one study found that Maternal Immune Activation due to E.Coli exposure during pregnancy alters offspring neuronal functioning through the alteration of ion channels and neuronal firing capabilities.⁸ In a different study, the focus shifted to the behavioral outcomes of MIA exposed offspring and it was found that the lasting behavioral and learning effects on offspring mice of maternal immune activation produced results consistent with the behavior demonstrated by Autism Spectrum Disorder individuals.⁹

Conclusion: Maternal Immune Activation stimulates the release of IFN–γ, activating the JAK-STAT pathway and stimulating chromatin remodeling which causes transcriptional changes. ⁵ Across numerous studies, these transcriptomic changes due to MIA overlap with gene expression profiles associated with ASD individuals. Additionally, behavioral changes of offspring MIA-exposed mice are consistent with behavioral traits associated with ASD. Understanding these changes and how to prevent them could create a path for preventing ASD.

Works Cited.

1.  Lord C, Brugha TS, Charman T, et al. Autism spectrum disorder. Nat Rev Dis Primers. 2020;6(1):5. Published 2020 Jan 16. doi:10.1038/s41572-019-0138-4
2. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther. 2018;190:91-104. doi:10.1016/j.pharmthera.2018.05.007
3. Ramaswami G, Geschwind DH. Genetics of autism spectrum disorder. Handb Clin Neurol. 2018;147:321-329. doi:10.1016/B978-0-444-63233-3.00021-X
4. Genovese A, Butler MG. Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD). Int J Mol Sci. 2020;21(13):4726. Published 2020 Jul 2. doi:10.3390/ijms21134726
5. Warre-Cornish K, Perfect L, Nagy R, et al. Interferon-γ signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes. Sci Adv. 2020;6(34):eaay9506. Published 2020 Aug 19. doi:10.1126/sciadv.aay9506
6. Kann O, Almouhanna F, Chausse B. Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration. Trends Neurosci. 2022;45(12):913-927. doi:10.1016/j.tins.2022.10.007
7. Kathuria A, Lopez-Lengowski K, Roffman JL, Karmacharya R. Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons. Brain Behav Immun. 2022;103:97-108. doi:10.1016/j.bbi.2022.04.007
8. Griego E, Segura-Villalobos D, Lamas M, Galván EJ. Maternal immune activation increases excitability via downregulation of A-type potassium channels and reduces dendritic complexity of hippocampal neurons of the offspring. Brain Behav Immun. 2022;105:67-81. doi:10.1016/j.bbi.2022.07.005
9. Amodeo DA, Lai CY, Hassan O, Mukamel EA, Behrens MM, Powell SB. Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex. Neurobiol Dis. 2019;125:211-218. doi:10.1016/j.nbd.2019.01.025
10. Flood L, Korol SV, Ekselius L, Birnir B, Jin Z. Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons. J Neuroimmunol. 2019;337:577050. doi:10.1016/j.jneuroim.2019.577050