The glutamate hypothesis of depression: a possible role for glutamate transporters in the pathophysiology of MDD

Major depressive disorder (MDD) is one of the most common psychiatric diseases, leading to diminished everyday functioning and inferior quality of life. Current neurobiological theories of depression focus on aberrant biogenic amine neurotransmission and almost all clinically used antidepressants target monoamine reuptake mechanisms and/or receptors. Unfortunately, a substantial proportion of patients do not respond to monoaminergic drugs. Furthermore monoaminergic mechanisms cannot entirely account for the downstream adaptations that could explain the lag time before onset of action of these monoaminergic drugs. One of the most exciting current avenues of investigation in this field is the role of glutamate in the pathophysiology of depression. Indeed, some ligands of glutamate receptors show antidepressant-like effects. Moreover recently glutamate transporters became targets of interest in the pathology of depression. Reduced brain expression of glutamate reuptake transporters in depressed humans as well as in a rat model for depression (Medina et al., Journal of Psychiatric Research, 2013 and Gomez-Galan et al., Molecular Psychiatry, 2012) was in line with a study showing that enhanced glutamate reuptake had antidepressant-like effects (Minneur et al., Biological Psychiatry, 2007).

The glutamate reuptake transporters (EAAT 1/2) and the cystine/glutamate antiporter (system xc- with specific light chain subunit xCT) are important mediators of extracellular glutamate levels. These proteins are located mainly on the astrocytes surrounding the synaptic cleft. EAATs are primordial for a swift glutamate clearance from the synapse, whereas system xc- is an important source of extrasynaptic glutamate. Since the glutamate transmission is disturbed in MDD, malfunctioning of these transporters could be a key factor in the pathophysiology. Furthermore pharmacological interaction with these proteins could prove helpful in the future clinical treatment of the disease.

To unravel the role of the EAATs and system xc- in MDD, we determine their protein expression levels in animal models for depression and human tissue. We have used the genetic Flinders Sensitive Line (FSL) ratmodel, from which we have dissected the most important depression-related brain areas. When comparing EAAT expression in FSL animals with their Sprague Dawley (SD) counterparts, we found a significant decrease in GLAST (EAAT 1 analogue in rodents) in the nucleus accumbens and hippocampus and a decrease of GLT-1 (EAAT 2 analogue) in the nucleus accumbens. In these brain regions there was no significant difference in xCT levels between FSL and SD rats. These findings suggest an important role for the EAAT dysfunctioning in the pleasure center (nucleus accumbens) and memory center (hippocampus) might contribute to the pathogenesis of MDD.
To further unveil possible malfunctioning in glutamatergic neurotransmission in MDD, we will next perform similar experiments in the corticosterone mousemodel and in post-mortem brain tissue from depressed patients.