BDNF signaling: Harnessing stress to battle mood disorder

Abstract

The link between the onset of major depressive disorder (MDD) and loss of neurotrophins in the brain is of interest to clinicians and basic scientists. MDD is caused by a combination of genetic, environmental, and psychological factors. Trauma, chronic health problems, and substance abuse are risks (1), as are grief and other purely emotional/cognitive stresses (2, 3). MDD alters the expression of neurotrophins, such as brain-derived neurotrophic factor (BDNF). BDNF is required for neuronal development, survival, and plasticity (4, 5). Brain imaging has shown volumetric changes in limbic regions in depression attributed either to reduced numbers of glia and pyramidal neurons or to their reduced cell body size, accompanied by atrophy of pyramidal neuron apical dendrites and decreases in neurogenesis in dentate gyrus (6). These structural alterations most likely contribute to features of depression, including cognitive impairment, helplessness, and anhedonia. Neuronal dysfunction also affects activation of the hypothalamic–pituitary–adrenal axis (7). Studies show that structural and functional neuronal alterations in MDD are partially rescued by antidepressant treatment. Antidepressants, in addition to their effects on neurotransmitter levels, also increase BDNF and enhance expression of the receptor for BDNF, tropomyosin-related kinase B (TrkB), in the hippocampus (8). However, the intracellular mechanisms governing the relationship between BDNF, structural changes in limbic system cells, and clinical manifestations of MDD are still unclear. In PNAS, Marshall et al. (9) demonstrate that Gαi1 and Gαi3, members of the GαI subclass of heterotrimeric G proteins, are essential for BDNF/TrkB signaling in hippocampus and are down-regulated by chronic stress. G proteins form membrane-associated heterotrimers consisting of α, β, and γ subunits (10). There are four main subclasses: Gs, Gi/o, Gq, and G12/13. GαI belongs to the Gi/o subclass and inhibits adenylyl cyclase. Marshall et al. report that reductions in … [↵][1]1To whom correspondence should be addressed. Email: elizabeth.jonas{at}yale.edu. [1]: #xref-corresp-1-1