Therapeutic potential of glutamatergic N-methyl-D-aspartate (NMDA) receptors-mediated molecules for autism spectrum disorders

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with marked variability in severity and phenotypic manifestation clinically. Abnormal synaptic connectivity is implicated as an important contribution to the pathogenesis of ASD because all ASD-related genes share deficits in synaptic dysfunction. In addition, previous human and animal model studies indicate that the expression, trafficking and fucntion of ionotropic glutamate receptors are altered, whcih result in altered synapse development and plasticity in a ASD-specific manner. To date, placeo-controlled clinical drug trials targeting the core social impairment of ASD have had negative results and the search for potentially novel agents targeting the core social impairment of autism continues. Since several recent findings provide evidence that the pathophysiology of ASD may include a component of glutamate receptor disruption, this is a line of thinking worthy of pursuit. In this review, we reported the evidences of abnormal glutamate metabolism in patients with ASD; brief introduction of the ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors; genetic animal models of NMDA receptor hypofunction and hyperfunction; the preclinical studies and the human clinical trials exploring the effects of the glutamatergic NMDA receptors modulating agents in the treatment of ASD which were identified on the Medline and Clinical Drug Trial registry system. In conclusion, the positive preclinical data with drugs believed to act via modulation of NMDA-mediated signalling encourage further exploration of this mechanism as a target approach for ASD. However, up to now, only a few glutamatergic compounds have been studied in clincial trials of ASD, and the results are inconclusive. The data suggest that targeting the NMDA receptor can have promising therapeutic potentials in ASDs. The complex relationship between glutamate-medicated signaling and the behavioral-cogniitive phenotype of ASD may be better elucidated in the future by combining the new cell-based models with well characterized subtype of ASD pateints.