Search

Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals' ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families. [ABSTRACT FROM AUTHOR]

Synaptic cell adhesion molecules (SynCAMs) are crucial for synapse formation and plasticity. However, we have previously demonstrated that SynCAMs are also required during earlier stages of neural circuit formation because SynCAMI and SynCAM2 (also known as CADM1 and CADM2, respectively) are important for the guidance of post-crossing commissural axons. In contrast to the exclusively homophilic cis-interactions reported by previous studies, our previous in vivo results suggested the existence of heterophilic cis-interactions between SynCAMI and SynCAM2. Indeed, as we show here, the presence of homophilic and heterophilic cis-interactions modulates the interaction of SynCAMs with trans-binding partners, as observed previously for other immunoglobulin superfamily cell adhesion molecules. These in vitro findings are in agreement with results from in vivo studies, which demonstrate a role for SynCAMs in the formation of sensory neural circuits in the chicken embryo. In the absence of SynCAMs, selective axon-axon interactions are perturbed resulting in aberrant pathfinding of sensory axons. [ABSTRACT FROM AUTHOR]

Synaptic cell adhesion molecules are characterized by their potential to trigger synaptogenesis in vitro, even when expressed in non-neuronal cell lines. In addition to the prototypic synaptic cell adhesion molecules ( Syn CAMs), other structurally unrelated families of synaptic cell adhesion molecules have been identified: neurexins and neuroligins, as well as the leucine-rich repeat transmembrane neuronal protein family. Although in vivo the absence of individual synaptic cell adhesion molecules does not necessarily reduce the number of synapses, it does affect the function of synapses. Not surprisingly, mutations in synaptic cell adhesion molecules have been identified in patients suffering from neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability or schizophrenia. In line with the major function of these genes at the synapse, their role in the pathogenesis of neurodevelopmental diseases has been attributed to synaptogenesis, synapse maintenance and synaptic plasticity. However, one family of synaptic cell adhesion molecules, the Syn CAMs, have also been implicated in axon guidance, that is, an earlier step in neural circuit formation. These findings suggest that Syn CAMs, and maybe other families of synaptic cell adhesion molecules as well, could contribute to the pathogenesis of neurodevelopmental disorders at multiple steps of neural circuit formation and, thus, shape the distinct symptoms associated with different disease variants or distinct neurodevelopmental disorders in addition to their effect on synaptic function. In this review, we summarize the roles of one family of synaptic cell adhesion molecules, the Syn CAMs, at the synapse and beyond in axon guidance and myelination. [ABSTRACT FROM AUTHOR]