Vagus nerve stimulation as an anti-inflammatory therapy for maternal immune activation-induced alterations in offspring microglia and neurodevelopment

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by a combination of genetic and environmental factors. With the increasing prevalence of ASD diagnosis, it is crucial to understand the mechanisms behind preventable causes, such as prenatal infections, and look for possible routes to improve outcomes. For example, maternal immune activation (MIA), the process by which immunogens that enter the maternal system lead to a maternal inflammatory response, has been well established as associated with increased ASD diagnosis. However, the mechanisms have not been fully elucidated and the options for targeting MIA as a preventative measure are uncertain. The maternal cytokine response is considered a crucial mechanism underlying MIA-induced neurodevelopmental changes, with key contributing cytokines, which include interleukin (IL)-6 and IL-17a. These cytokines can be produced in the maternal periphery and placenta, leading to the transmission of maternal cytokines into the fetal brain and causing upregulation of endogenous production. In the fetal brain, IL-6 and IL-17a act on microglia, the innate immune cells of the central nervous system, to further induce pro-inflammatory cytokine production. Furthermore, microglia alter fetal brain neurocircuitry, leading to lifelong, ASD-like dysregulation. The vagus nerve, the primary nerve of the parasympathetic nervous system, may serve as a target for intervention. The cholinergic anti-inflammatory pathway can be targeted by vagus nerve stimulation (VNS) and can lead to the downregulation of peripheral cytokines. This review is intended to summarize the cytokine-related mechanisms of MIA, the role of fetal microglia in dysregulation, and to assess the potential for VNS as a preventative treatment measure for MIA-induced alterations.