Vanessa Alkarra

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, affecting approximately 2.2% of adults in the US, and has been increasing in prevalence.¹ ASD is characterized by persistent social deficits and repetitive/stereotyped behaviors and its etiology consists of genetic and environmental components. However, mechanisms of ASD pathogenesis are under investigation and require further elucidation.² Evidence suggests that immunological dysfunction may play a role in its development as significant associations between immune abnormalities and ASD have been observed.² Specifically, Maternal Immune Activation (MIA), inflammation during pregnancy as a result of viral or bacterial infections, is a risk factor for ASD and may contribute to its pathogenesis through multiple mechanisms.² Thus, investigations into the role of MIA in ASD development may further elucidate its etiology and indicate potential therapeutic targets.

Objective: The goal of this review was to evaluate the mechanisms by which MIA contributes to ASD pathogenesis and investigate potential therapeutic targets for MIA-induced ASD.

Search Methods: Filtering for publications from 2017 to 2024, an online search was conducted on the PubMed database using the search terms: “autism,” “autism spectrum disorder,” “maternal immune activation,” and “immune function.”

Results: In MIA-induced rat offspring, studies found significant upregulation of proinflammatory cytokines, IL-6, TNF-alpha, IFN-gamma, and oxidative factors, COX-2 and 12-LOX, compared to controls.^2,4,6 Moreover, MIA offspring demonstrated microglial activation and synaptic alterations in the cerebellum and hippocampus.^2-4,6 Studies reported a significant decrease in cerebellin-1 and glutamate receptor delta 2, proteins involved in maintaining synapses in the cerebellum, and reductions of key SNARE complex proteins, synaptobrevin1/2 and syntaxin-1, involved in synaptic vesicle formation in the cerebral cortex of MIA offspring.^2-4 Morphological changes in synapses were also observed, including nerve-ending swellings, reduced density of synaptic vesicles, and disruptions in synaptic membrane integrity.⁴ Furthermore, MIA generated cortical patches in the dysgranular zone of the primary somatosensory cortex (S1DZ) that displayed loss of Parvalbumin (PV) expression, a class of inhibitory interneurons implicated in neurodevelopmental disorders.⁵ Cortical patch size correlated with phenotype severity in MIA offspring, and activation of PV interneurons recapitulated ASD phenotypes in wild-type offspring.⁵ Lastly, administration of exogenous programmed cell death ligand 1 (PD-L1) reduced the impact of neuroinflammation on MIA offspring, generating a less severe ASD phenotype.⁶

Conclusion: Investigations suggest that MIA contributes to ASD pathogenesis in rat and mouse offspring through neuroinflammation, microglial activation, changes in synaptic expression in the cerebellum and hippocampus, and generation of cortical patches in S1DZ.^2-6 Administration of PD-L1 demonstrated a preventative effect in MIA-induced ASD phenotypes, indicating its potential for therapeutic use.⁶ More investigations into MIA-induced ASD are required to further elucidate its etiology and identify potential therapeutic targets that may mitigate MIA’s impacts on offspring neurodevelopment.

Works Cited:

1. Hirota T, King Autism Spectrum Disorder: A Review. JAMA. 2023;329(2):157-168. doi:10.1001/jama.2022.23661
2. Pendyala G, Chou S, Jung Y, et Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression. Neuropsychopharmacology. 2017;42(7):1435-1446. doi:10.1038/npp.2017.7
3. Fernández de Cossío L, Guzmán A, van der Veldt S, Luheshi Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring. Brain Behav Immun. 2017;63:88-98. doi:10.1016/j.bbi.2016.09.028
4. Cieślik M, Gąssowska-Dobrowolska M, Jęśko H, et al. Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Int J Mol Sci. 2020;21(11):4097. doi:10.3390/ijms21114097
5. Shin Yim Y, Park A, Berrios J, et Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature. 2017;549(7673):482-487. doi:10.1038/nature23909
6. Zeng X, Fan L, Qin Q, et Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice. Brain Behav Immun. 2024;122:527-546. doi:10.1016/j.bbi.2024.08.042