Glutamate Signaling Defects in Propionic Acid Orally Administered to Juvenile Rats as an Experimental Animal Model of Autism

A high extracellular concentration of glutamate has the potential to induce autism. Presently no appropriate treatment is available to modulate glutamate-mediated injury; however, increased levels of glutamate transporters, which aid in glutamate clearance, may potentially limit and prevent glutamate excitotoxicity, and β-lactam antibiotics have been found to activate the expression of a glutamate transporter. To identify the beneficial role of β-lactam in autism, we used an animal model of autism by administrating propionic acid (PPA) to juvenile rats and then treated these animals with this antibiotic. Animals were divided into three groups: (1) an untreated control group, (2) a PPA-intoxicated group and (3) a PPA-intoxicated group treated with β-lactam. Selected parameters related to glutamate signaling were measured in brain homogenates of all groups. The obtained data demonstrated neurotoxicity of PPA through glutamate (GLU) excitotoxicity. Moreover, the rats treated with β-lactam exhibited higher glutamate transporter 1 (Glt-1) levels than the control group (p = 0.044). Furthermore, compared to the expression in the control group and the untreated autism model group, Glt-1 gene expression was much higher in brain samples from β-lactam-treated autism model rats (p < 0.056). Receiver operating characteristic (ROC) analyses revealed that measured parameters such as GLU and GLU/γ-aminobutyric acid, Glt-1, and GLU/Glt-1 were found to be predictive markers of the protective effect of β-lactam against GLU excitotoxicity. Immediate upregulation of Glt-1 may reduce extracellular GLU levels and thereby prevent damage to neurons. Therefore, increasing Glt-1 expression could be a potential approach to prevent excitotoxicity in the brain.