Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Abstract

Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na⁺-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.

Keywords: Affective disorders; Excitatory amino acid transporter; Glia; Glutamate; Glutamate transporter; Psychiatry; Schizophrenia.

Figure 1

The metabolic fate of glutamate in glia cells. Glutamate is released from the pre-synaptic neuron to induce activation of the post-synaptic neuron via GluR. Spill-over of excess glutamate from the synaptic cleft is prevented through uptake by glial glutamate transporters EAAT1 and EAAT2, following which glutamate is converted to glutamine by GS for recycling back into glutamate, or α-KG for entrance into the tricarboxylic acid cycle. AAT: Aspartate Aminotransferase; α-KG: Alpha ketoglutarate; EAAT1/2: Excitatory amino acid transporter 1 and 2; GLDH: Glutamate dehydrogenase; Gln: Glutamine; GLS: Glutamate synthase; GS: Glutamine synthase; Glu: Glutamate; GluR: Glutamate receptors; Na+: Sodium; K+: Potassium.