EAAT2 as a Research Target in Bipolar Disorder and Unipolar Depression: A Systematic Review.

Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992-January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levels in vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.