Perturbed synaptic adhesion molecules signaling in neurodevelopmental disorders: The impact of metal neurotoxicity

Synaptic adhesion molecules (SAMs) are glycoproteins localized on neuronal surfaces, primarily expressed at synaptic plasma membranes. SAMs play a role in inducing formation, maturation, plasticity, and assembly of synaptic connections, which are vital for normal neurodevelopment. SAMs link the pre- and post-synaptic compartments and assist in inter-synaptic signaling and recognition. An increasing variety of SAMs, including neurexins and neuroligins, immunoglobulin (Ig) domain proteins-like synaptic cell adhesion molecule (SynCAM) and neural cell adhesion molecule, receptor phosphotyrosine kinases and phosphatases, as well as various leucine-rich repeat proteins, have been identified. Neurodevelopmental disorders (NDDs), like autism, attention deficit hyperactivity disorder, intellectual disabilities, and cerebral palsy, have been associated with altered SAMs. NDDs are characterized by a spectrum of challenges stemming from abnormal brain development. The etiology of these disorders involves the interaction between genes and environmental factors, such as metals. This review aims to provide a comprehensive overview of the literature, highlighting the role of SAMs in NDDs and potential mechanisms via which neurotoxic metals may contribute to the pathogenesis of NDDs that could involve perturbations in SAMs. Understanding these interconnections will assist in identifying therapeutic targets for these disorders.