Figure 1.

A schematic representation showing effects of monoamines and antidepressants on astrocytes, which are relevant to their antidepressant action. Classical antidepressants lead to increase in synaptic concentrations of monoamines, depicted here is norepinephrine (1). Activation of β-adrenoreceptors by norepinephrine can lead to upregulation of CREB-mediated transcription through adenylyl cyclase/PKA activation (2). This increases the expression of BDNF (3), which can, in turn, increase the expression of other trophic factors, namely, VGF and VEGF. Antidepressant may also increase trophic factor expression in astrocytes through yet unknown mechanisms (4). For instance, antidepressants are known to decrease the activity of an inward rectifying potassium channel (Kir4.1) (5), and a decrease in Kir4.1 activity or expression decreases BDNF expression (6). These trophic factors can then enhance adult hippocampal neurogenesis, thus aiding the behavioral effects of chronic antidepressant treatments (7). BDNF also enhances excitatory transmission by increasing vesicle docking and enhancing quantal release from glutamatergic presynaptic terminals (8). Trophic factors also enhance excitatory postsynaptic responses through various mechanisms (9). BDNF increases the expression of various NMDA receptor subunits and mediates the phosphorylation of NR2B. It is also known to enhance actin polymerization. In addition, both BDNF and VEGF are known to promote LTP. Moreover, BDNF and VGF mediate dendritic outgrowth which can rescue volumetric loss observed in depressive disorders. Norepinephrine and several antidepressants are also shown to induce breakdown of glycogen through α₂- and β-adrenoreceptors in astrocytes (a). This results in increase in glycolytic activity and production and secretion of lactate by astrocytes (b). Lactate, apart from acting as an energy substrate in neurons, is also known to increase NMDA currents, LTP, and plasticity-related gene expression, including expression of BDNF (c). BDNF indicates brain-derived neurotrophic factor; CREB, CRE-binding protein; LTP, long-term potentiation; PKA, protein kinase A; VEGF, vascular endothelial growth factor.