Glutamatergic agents in Autism Spectrum Disorders: Current trends

Glutamate transmission dysfunction has been found in various preclinical models of Autism Spectrum Disorders (ASD), thus the glutamate system is a target for therapeutics. This report reviews current treatments for glutamate dysfunction in ASD models and clinical trials. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5) have been tested in preclinical models of autism. Black and Tan Bachyuric (BTBR) mice model behavioral phenotypes of the three core diagnostic domains of autism, e.g. social deficits, impaired language and communication, and repetitive behaviors. A significant reduction in repetitive self-grooming was observed after mGluR5 antagonist administration in BTBR mice. SHANK 3 deficient mice which have altered synaptic transmission and plasticity, were administered IGF-1 treatment to reverse these deficits based on the hypothesis that reduced AMPA receptor levels reflect less mature synapses. Clinical trials have been carried out in ASD with glutamate NMDA receptors, but current findings are not sufficient for conclusions on safety and efficacy. Memantine is an NMDA antagonist under investigation in controlled trials that hopefully will provide new insight on its use in autism. Studies using novel treatments with other glutamatergic agents are also underway and encouraging results have been observed with N-acetylcysteine in treating irritability in ASD.