Neuroimmune mechanisms in autism etiology - untangling a complex problem using human cellular models

Abstract

ASD affects 1 in 36 people and its core features are impaired sociability, the presence of repetitive behaviors and deficits in verbal communication. While most ASD cases are of genetic origin there is a large number of cases that are of complex or unknown etiology, which suggests the potential for environmental risk factors to influence ASD pathogenesis. In fact, a large number of studies that include epidemiology and animal studies suggest that severe infections during pregnancy could lead to a higher risk of ASD in the progeny. However, studies in human experimental systems that allow for the dissection of precise mechanisms during early brain development which could be affected due to inflammation have been lacking. Stem cell technology gives us the opportunity to study the early stages of human brain development. Here we broadly discuss clinical, epidemiological, and mechanistic studies that focus on the effect of inflammation in the developing brain, and we review recent work using iPSC-based models that study how pre-natal inflammation during the early stages of brain development could increase ASD risk.

ABSTRACT

Autism spectrum disorder (ASD) affects 1 in 36 people and is more often diagnosed in males than in females. Core features of ASD are impaired social interactions, repetitive behaviors and deficits in verbal communication. ASD is a highly heterogeneous and heritable disorder, yet its underlying genetic causes account only for up to 80% of the cases. Hence, a subset of ASD cases could be influenced by environmental risk factors. Maternal immune activation (MIA) is a response to inflammation during pregnancy, which can lead to increased inflammatory signals to the fetus. Inflammatory signals can cross the placenta and blood brain barriers affecting fetal brain development. Epidemiological and animal studies suggest that MIA could contribute to ASD etiology. However, human mechanistic studies have been hindered by a lack of experimental systems that could replicate the impact of MIA during fetal development. Therefore, mechanisms altered by inflammation during human pre-natal brain development, and that could underlie ASD pathogenesis have been largely understudied. The advent of human cellular models with induced pluripotent stem cell (iPSC) and organoid technology is closing this gap in knowledge by providing both access to molecular manipulations and culturing capability of tissue that would be otherwise inaccessible. We present an overview of multiple levels of evidence from clinical, epidemiological, and cellular studies that provide a potential link between higher ASD risk and inflammation. More importantly, we discuss how stem cell-derived models may constitute an ideal experimental system to mechanistically interrogate the effect of inflammation during the early stages of brain development.