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.