The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics

Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.