From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders

Abstract

Several structural and cellular changes, including marked glial anomalies, have been observed in association with major depressive disorder. Here we review these cellular alterations and highlight the importance of glial cell pathology, especially astroglial dysfunction, in the pathophysiology of neuropsychiatric disorders with a particular interest in major depressive disorder. The functional role of astrocytes in glutamate uptake and glutamate/glutamine cycling is discussed, as is the deleterious effects of chronic stress on glial cell function. Lastly, we discuss the effect of antidepressants on glial cell function and the possibility of targeting glial cells in the quest to develop novel therapeutics.

Figure 1. Neuron-Glial interactions within the tripartite synapse

Glutamate is released from vesicles within presynaptic neurons on excitation. Once released the glutamate can activate a variety of ionotropic and metabotropic receptors on postsynaptic and presynaptic neurons as well as glial cells. Some additional glutamate is released into the extracellular space through the cystine/glutamate transporter (xc-) on glial cells. Glutamate is cleared from the extracellular space via high-affinity excitatory amino acid transporters (EAATs), which are located primarily on neighboring glial cells (EAAT1-2) and, to some extent, on neurons (EAAT 3). In glial cells, glutamate is converted into glutamine by glutamine (Gln) synthetase. Glutamine is then transported back into the glutamatergic neuron, where it is hydrolyzed into glutamate by glutaminase. Glial cells also provide metabolic and energy support to neurons through a supply of lactate. Additionally, Serine racemase, the D-serine-synthesizing enzyme, is expressed by astrocytes. On release, D-Serine serves as a co-agonist at NMDA receptors. Astroyctes serve additional critical physiological roles through the synthesis and release of several neurotrophic factors including glial derived neurotrophic factor and brain derived neurotrophic factor.

Figure 2

Stress and depression are associated with altered glutamate release and uptake that maybe be targeted by antidepressant development. Preclinical and clinical studies demonstrated atrophy and loss of astrocytes related to depression and animal models of depression. Astroglial anomalies include reduced EAAT2 (GLT1), glutamate metabolism and glial function. Some of these changes could be reversed by treatment with drugs that enhance EAAT2 expression, trafficking or activity such as riluzole or ceftriaxone. Identifying other drugs able to block or reverse stress-induced glial alterations could open a new avenue for antidepressant development.