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.

Keywords: autism spectrum disorder; cell adhesion molecules; glial cells; inflammatory cascade; neuroinflammation; neuroinflammatory signaling.

FIGURE 1

The relationship between autism spectrum disorder (ASD), inflammation, and cell adhesion molecules (CAMs). Neuronal CAMs such as the CNTN, CNTNAP, NCAM, NRXN, NLGN, and NFASC families of proteins are consistently implicated as risk genes for ASD (9, 16). Likewise, inflammation, particularly in MIA, has been identified as an environmental risk factor for ASD (24, 31). What is yet unclear is whether these neuronal CAMs may be involved in regulating inflammatory responses or cascades in ASD. Contactin (CNTN), CNTN-associated protein (CNTNAP), neural cell adhesion molecule (NCAM), neurexin (NRXN), neuroligin (NLGN), neurofascin (NFASC), and maternal immune activation (MIA). Created with BioRender.com.

FIGURE 2

Neuroinflammatory pathways in prenatal and postnatal neurodevelopment contributing to autism spectrum disorder (ASD). (A) Neuroinflammatory pathways in prenatal neurodevelopment. Contactin-1 (CNTN1), expressed on the surface of oligodendrocyte precursor cells (OPC) promotes OPC differentiation to oligodendrocytes by interacting with receptor protein tyrosine phosphatase zeta (PTPRZ) (250, 258). Simultaneously, OPC proliferation is inhibited by the same PTPRZ interaction (250). The transfer of maternal proinflammatory cytokines such as interleukin (IL)-6 and IL-17 via maternal immune activation can promote neuroinflammation during prenatal neurodevelopment (115, 121). As a result, increased receptor IL-17 (IL-17R) expression is found within the fetal brain, enhancing further neuroinflammatory signaling (107). Although there is some evidence for autoimmune antibodies in association with ASD, their origin and effect on neuroinflammation in the developing ASD brain is unclear (140). (B) Neuroinflammatory pathways in postnatal neurodevelopment. Astrocytes are activated by proinflammatory cytokines and neuroinflammation in the central nervous system (227). Neural cell adhesion molecule-1 (NCAM1) expressed on the surface of astrocytes can activate nuclear factor-κB (NF-κB)-mediated transcription of proinflammatory genes (123). NCAM1 can also inhibit astrocyte proliferation through the inhibition of mitogen-activated protein kinase (MAPK) signaling (237). Changes to OPC proliferation have been observed in ASD brains, which can alter the production of myelin and possibly expose neuronal cells to inflammatory insult (146). Microglia are also activated by proinflammatory cytokines and neuroinflammation in the central nervous system (220). Activated microglia to produce proinflammatory cytokines including IL-1β and tumor necrosis factor (TNF)-α (39). Created with BioRender.com.