Magnetic Resonance Spectroscopy Studies of Glutamate and GABA in Autism: Implications for Excitation-Inhibition Imbalance Theory

Abstract

One popular major theory of neurotransmitter dysfunction is an imbalance in excitation and inhibition (EI theory).The EI imbalance theory is thought to impact widely across neural circuits mediating language, social, and cognitive functions, and could potentially explain some aspects of the autism phenotype. Evidence from genetic and molecular studies provide support for abnormal suppression of γ-aminobutyric acid (GABA) function and an overabundance of glutamatergic transmission as potential mechanisms of this hyperexcitability. Proton magnetic resonance spectroscopy (1H-MRS) is a potentially exciting neuroimaging tool allowing in vivo estimation of glutamate and GABA neurotransmitters in people with autism spectrum disorder (ASD). We reviewed all available published studies of ASD reporting 1H-MRS measurement of glutamate, GABA, or both neurotransmitters. Glutamate results across studies are equivocal, with nearly equal numbers of studies reporting increases or decreases in autism. However, the age of the individuals studied appears to relate to the direction of the findings, suggesting that future longitudinal studies of glutamate should be conducted. Although fewer GABA-specific studies have been published, all have reported decreases in autism. Overall, from 1H-MRS studies alone, support for the glutamate side of the EI imbalance theory is tenuous, but this is an indication of serious limitations in the 1H-MRS literature. For GABA dysfunction, the GABA findings to date are consistent for reduced concentration in autism; however, there are only a few published 1H-MRS studies of GABA in autism, all from studies with a small number of subjects. More studies, particularly longitudinal developmental studies across both child and adult development, are needed.