The molecular neurobiology of depression

Abstract

Depression is a condition with a complex biologic pattern in etiology. Environmental stressors modulate subsequent vulnerability to depression. In particular, early adversity seems to induce heightened reactivity to stress through several possible mechanisms, both biologic and psychologic. This increased reactivity results in an enhancement of biologic stress-response mechanisms, especially the HPA axis. Regulators of this system, particularly signal transduction pathways involving PKA and PKC, may be important in the regulation of key genes in this system including genes for GR, BDNF, and trk-b. This system potentially is vulnerable to ROS and therefore, indirectly, to the effects of cytokines. Finally, some of these effects may be controlled by chemical modification of DNA, specifically, methylation of promoters or other gene regions. This modification is a mechanism by which long-term biologic change can be induced by environmental stressors. The brain is homeostatic, and it is possible that alterations at multiple points in this system may induce dysregulation and, as a result, vulnerability to stress. Therefore, a person may be vulnerable to depression, which may be a final common "pathway" for this family of conditions. Individuals may very considerably with regard to the locus of the problem, however. For example, functional variants in a set of genes might predispose some people to depression; others may have epigenetic imprinting; and yet different causes may be at work in others. Although this mix is complicated, it can be unraveled. Doing so could lead to the development of novel interventions that could target specific points of vulnerability, allowing an improved matching of patient to treatment based on differential abnormalities at the cellular level.

Figures

Figure 1

Protein kinase A activity in depressed patients and normal controls. Panel A: Activity in the total group, depressed and controls. Panel B: Activity in depressive subtypes and controls.(5)

Figure 2

Representative intracellular g-protein coupled signal transduction cascades. Subheading: Cell surface receptors, such as norepinephrine ß receptors, are coupled to stimulatory G (Gs) proteins. On transmitter binding, Gs activates adenylate cyclase (AC), catalyzing the formation of cyclic AMP from ATP ➀. Cyclic AMP is degraded to AMP by phosphodiesterases (PDE), which inactivate the cyclic AMP signal ➁. Cyclic AMP binds to the regulator subunits (R) of protein kinase A (PKA), resulting in a conformational change and the release of two catalytic subunits (C) ➂. The C subunits then are capable of phosphorylating serine and threonine residues on target polypeptides. One such protein is cyclic AMP response element binding protein (CREB), a transcriptional factor ➃. Phosphorylation of CREB results in translocation of CREB-P to the nucleus and subsequent binding to CRE-containing gene promoter regions activating expression ➄. A parallel pathway, exemplified by the 5-HT2A transductional cascade, couples to Gq (another stimulatory G protein), activating phospholipase C (PLC) catalyzing the conversion of phosphotidylinositol (PI) to diacylglycerol (DAG) and inositol triphosphate (IP3) ➅. IP3 mobilizes Ca2+ release from intracellular stores. DAG binds to protein kinase C resulting in phosphorylation of target proteins; these include both CREB and PKA ➆. The phosphorylation of PKA regulates the activity of the enzyme. Phosphorylated substrates are subsequently dephosphorylated by protein phosphatase 2A ➇. On dephosphorylation, CREB returns to the cytosol. Another regulator of PKA activity is protein kinase inhibitor (PKI); in the case of fibroblasts, this is the PKIγ isoform ➈. Both PKA and PKC can be glutathionylated, protecting them from oxidative degradation ➉. The activation loops of both enzymes are phosphorylated by phosphoinositide dependent kinase 1 (PDK1)