Cellular and synaptic network defects in autism

Many candidate genes are now thought to confer susceptibility to autism spectrum disorders (ASDs). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs.

► Mutations in several genes encoding the core transsynaptic complex of Neurexin/Neuroligin/PSD-95/SAPAP/Shank confer susceptibility to ASDs. ► Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and synaptic ASD candidate genes have overlapping interaction networks. ► Mouse models for ASDs have helped identify commonalities in glutamatergic dysfunction. ► Identifying important nodes in interaction networks may facilitate therapeutical intervention. ► ASD endophenotypes may be triggered by common neural circuit defects.