Glutamate-mediated signaling and autism spectrum disorders: emerging treatment targets

Autism spectrum disorders (ASD) are developmental disorders that are characterized by deficits in reciprocal social interactions and communication, as well as by the presence of impairing repetitive behaviors and restricted interests. Prior work examining human pathology, and model systems and genetic studies have all led to the current conceptualization of ASD as a disorder of synaptic formation and functioning (a "synapsopathy"). In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission, with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of the structure and function of glutamate receptors, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the development of novel drugs for ASD treatment, and reports on glutamate- related clinical trials. We will also present promising new techniques using human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotypes, cellular responses and glutamate involvement in ASD.