2026 ECNP Congress

PS04-4017

Early IL-17A blockade prevents autism-like behavioural and molecular abnormalities in a maternal immune activation mouse model

Giorgia Macchioni — M.S. Spagnuolo, N. Petecca, G. Petruccioli, M. De Magistris, M. Auricchio, F. De Palma, M. Prisco, C. Cipriani, M. Siracusano, G. Calamandrei, L. Ricceri, L. Cigliano, A.M. Tartaglione · Istituto Superiore di Sanità, Centre for Behavioural Sciences and Mental Health, Roma, Italy

2026 ECNP Congress

Background

Autism Spectrum Disorder (ASD) is an early-onset neurodevelopmental condition marked by impairments in social communication and interaction, alongside repetitive behaviours [1]. Growing evidence implicates immune dysregulation in its pathogenesis, with maternal infection during early pregnancy representing a significant environmental risk factor [2]. Preclinical studies indicate that infections during pregnancy and resulting maternal immune activation (MIA) increases pro-inflammatory cytokines that can cross the placenta and affect fetal brain development, leading to persistent neuroinflammation and ASD-like neurobehavioural abnormalities in offspring [3]. Among these mediators, interleukin-17A (IL-17A), released by T helper 17 cells, has emerged as a key contributor to MIA-induced phenotypes [4]. However, the potential efficacy of early IL-17A blockade in preventing MIA-induced alterations has not been fully explored.

A****im: We evaluated whether early administration of IL-17A antibody shortly after MIA induction could mitigate ASD-like behavioural and molecular alterations in male and female mouse offspring.

Methods

MIA was induced in pregnant mice by a single intraperitoneal (i.p.) injection of polyinosinic:polycytidylic acid [Poly(I:C), 20 mg/kg], a double-stranded RNA analog, on gestational day 12.5, while control dams received saline. Twenty-four hours later, mice were injected with either an IL-17A antibody (anti-IL-17A) or an isotype control (500 µg, i.p.). Offspring of both sexes were divided into three developmental cohorts (neonatal, early adolescence, and late adolescence), each tested with a tailored behavioural battery targeting core ASD-like features, including social deficits and repetitive behaviours, as well as comorbidities such as anxiety-like behaviour. To further characterise MIA-induced molecular changes and the potential efficacy of anti-IL-17A treatment in preventing these effects, hippocampal synaptic and neuroinflammatory markers were analysed at postnatal day 28, a critical period of synaptic pruning and stabilisation in rodents. Protein levels of synaptic markers and inflammatory mediators were assessed using ELISA and Western blot. Depending on data distribution, statistical analyses were performed using either a three-way ANOVA or a Kruskal–Wallis test, followed by Tukey’s or Dunn’s tests, respectively. Social preference was further assessed using one-sample t-tests against chance level (50%), followed by Bonferroni correction.

Results

Prenatal administration of anti-IL-17A significantly reduced repetitive behaviours selectively observed in MIA male offspring (p < 0.05) and mitigated social deficits emerging in late adolescence in both sexes (p < 0.05). Importantly, anti-IL-17A administration prevented early MIA-induced alterations in key mediators of synaptic plasticity in both sexes, including brain-derived neurotrophic factor and synaptic proteins (SNAP-25, synaptotagmin I, and PSD-95), as well as glutamate receptor NMDA (all p < 0.01). It also prevented neuroinflammatory changes, including NF-κB activation (p < 0.01) and increased levels of pro-inflammatory cytokines (TNF-α, IL-6 and IL-17A; all p < 0.01), suggesting a restoration of synaptic and neuroimmune pathways.

Conclusions

Early and precisely timed blockade of IL-17A (24h after MIA induction) may attenuate ASD-like behavioural and neurobiological abnormalities in offspring, supporting IL-17A as a potential target within MIA-related neuroimmune pathways.

References

  1. American Psychiatric Association, 2013. Diagnostic and statistical manual of mental disorders, fifth ed. American Psychiatric Association Publishing, Washington.
  2. Kwon, H.K., Choi, G.B., Huh, J.R., 2022. Maternal inflammation and its ramifications on fetal neurodevelopment. Trends in immunology 43, 230-244.
  3. Malkova, N.V., Yu, C.Z., Hsiao, E.Y., Moore, M.J., Patterson, P.H., 2012. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, behavior, and immunity 26, 607-616.
  4. Choi, G.B., Yim, Y.S., Wong, H., Kim, S., Kim, H., Kim, S.V., Hoeffer, C.A., Littman, D.R., Huh, J.R., 2016. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933-939.