Preclinical/mechanistic investigations have been conducted into the aetiopathophysiology of impaired gliogenesis, gliotoxicity, and/or altered synaptic function in depressive disorders. As with SUDs, decreased synaptic glutamate reuptake, synaptic spillover, and extrasynaptic glutamate receptor stimulation were the hypothesized substrates of glutamatergic dysfunction. In rat models, expression of EAAT1/GLAST, EAAT2/GLT-1, EAAT4, and vGluT1 (a vesicle-bound glutamate transporter) is suppressed (Zink et al. 2010; Gourley et al. 2012). Decreased expression of these transporters coincides with increased levels of d-serine (a differential partial agonist at the glycineB coagonist site on the N-methyl-d-aspartate (NMDA) receptor (Sheinin et al. 2001)), which attenuates excitotoxic extrasynaptic stimulation (Papouin et al. 2012; Gomez-Galan et al. 2013). Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor membrane localization and activation may also be critical in treatment response to mood stabilizers (Du et al. 2007) and the NMDA receptor antagonist ketamine (Maeng et al. 2008). Finally, the glutamate-modulating drug riluzole stimulates astrocytic glutamate reuptake via EAAT2/GLT-1 upregulation and reverses both glial cell metabolic impairments and GFAP mRNA expression in CUS-exposed rats (Banasr et al. 2010; Gourley et al. 2012).
