Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.

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“…Abnormally elevated levels of IL-1β, IL-6, IL-8, and IL-17 have been found in studies of in patients with ASD of all ages [56]. In mouse models, ASD behaviour has been observed in the offspring of mice exposed to lipopolysaccharide, Il-17, and polyinosine polycytidylic acid during pregnancy [56]. Researchers also highlight the role of neural cellular adhesion molecule (NCAM)1, which appears to regulate nuclear factor kappa B (NF-κB) transcription in neurons, altering pro-inflammatory signalling [56].…”

“…Autism spectrum disorder (ASD) is another comorbid condition that may occur alongside AD. ASD has an unknown aetiology, yet the exposure to the combination of genetic and environmental factors, both prenatally and postnatally, is likely to contribute to the pathogenesis of ASD by influencing brain development [56]. One of the environmental factors considered in the pathogenesis of ASD is neuroinflammation [56].…”

“…ASD has an unknown aetiology, yet the exposure to the combination of genetic and environmental factors, both prenatally and postnatally, is likely to contribute to the pathogenesis of ASD by influencing brain development [56]. One of the environmental factors considered in the pathogenesis of ASD is neuroinflammation [56]. Abnormally elevated levels of IL-1β, IL-6, IL-8, and IL-17 have been found in studies of in patients with ASD of all ages [56].…”

“…One of the environmental factors considered in the pathogenesis of ASD is neuroinflammation [56]. Abnormally elevated levels of IL-1β, IL-6, IL-8, and IL-17 have been found in studies of in patients with ASD of all ages [56]. In mouse models, ASD behaviour has been observed in the offspring of mice exposed to lipopolysaccharide, Il-17, and polyinosine polycytidylic acid during pregnancy [56].…”

“…In mouse models, ASD behaviour has been observed in the offspring of mice exposed to lipopolysaccharide, Il-17, and polyinosine polycytidylic acid during pregnancy [56]. Researchers also highlight the role of neural cellular adhesion molecule (NCAM)1, which appears to regulate nuclear factor kappa B (NF-κB) transcription in neurons, altering pro-inflammatory signalling [56]. Moreover, NCAM1 and contactin-1 can mediate the proliferation of astrocyte and oligodendrocyte precursors, altering the neuroimmune response [56].…”