Dina Sharhan

Introduction. Autism spectrum disorders (ASD) are multifactorial neurodevelopmental conditions characterized by varying deficits in social interaction (1). Incidence of ASD has increased dramatically over the past decade, and it is now estimated to affect 1 in 59 americans (2). Heterogeneity of ASD symptoms is thought to result from interplay of genetic and environmental factors. The dramatic increase in the prevalence of ASD suggests that environmental insults play an important role in ASD etiology (3). Effect of maternal immune activation (MIA), resulting from inflammatory stimuli such as viral infections during pregnancy, on the development of the brain is an important factor to consider. Studies of MIA mice models have demonstrated cerebellar pathologies and altered behavioral phenotypes relevant to ASD (3). Specifically, loss of cerebellar Purkinje cells (PCs) is seen in both MIA models and ASD (4,5). MIA-induced abnormalities are thought to be due to changes of brain pro-inflammatory cytokines. A recent study has shown that MIA induces increased placental IL-6 signaling causing an amplified IL-6 expression in the developing cerebellum (6). Understanding the effects of MIA on maternal-placental-fetal communication can lead to advances in the prevention and treatment of ASD. Methods. Placental IL-6 receptor knockout mouse model was generated using Cre recombinase (Cre+). Fetal immune-response, neuropathology and behavior in Cre+ and Cre- models were assessed after injecting pregnant mice with poly(I:C) in the MIA group or saline in the control group on embryonic day 12 (5 6). Fetal brains were harvested within 24 hrs post-injection. IL-6 expression was measured using quantitative PCR. Cerebellar PCs were visualized using Calbindin immunofluorescence-staining. Behavioral abnormalities were assessed using 3-chamber social and marble-burying tests at 7 weeks of age (6). Results. MIA was found to increase IL-6 expression and reduce calbindin+ cerebellar PCs in Cre-, but not Cre+, MIA-exposed brains when compared to control (6). MIA Cre+ offspring displayed social preference similar to that in the control group, where they spent more time in the mouse chamber than the object chamber. However, MIA-exposed Cre- offspring showed no social preference. Increased repetitive marble-burying behavior was seen in MIA Cre-, but not Cre+, offspring when compared to controls. Conclusion. Knockout of placental IL-6 receptor in MIA- exposed mice prevents increase in brain IL-6 expression, loss of cerebellar PCs, and behavioral abnormalities observed in MIA models and ASD6. Blocking placental IL-6 signaling during the acute phase of maternal infection can serve as a preventative therapeutic for the development of neuropathological and behavioral symptoms of ASD in at-risk populations.

1.  Masi, Anne. An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options.
   Neuroscience Bulletin. 2017; 33(2): 183–193.
2. Perihan, Celal. Effects of Cognitive Behavioral Therapy for Reducing Anxiety in Children with High Functioning ASD: A Systematic Review and Meta-Analysis. J Autism Dev Disord. 2019. https://doi.org/10.1007/s10803-019-03949-7
3. Careaga, Milo. Maternal immune activation and autism spectrum disorder: From rodents to nonhuman and human primates. Biological Psychiatry. 2017; 81(5): 391-401.
4. Peter S, Ten Brinke MM, Stedehouder J, et al. Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nat Commun. 2016; 7:12627.
5. Shi L, Smith SE, Malkova N, Tse D, Su Y, Patterson PH. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav Immun. 2018; 23(1):116–123.
6. Wu WL, Hsiao EY, Yan Z, Mazmanian SK, Patterson PH. The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun. 2016; 62:11–23.