Perisynaptic astrocytes as a potential target for novel antidepressant drugs

Emerging evidence suggests that dysfunctions in glutamatergic signaling are associated with the pathophysiology of depression. Several molecules that act on glutamate binding sites, so-called glutamatergic modulators, are rapid-acting antidepressants that stimulate synaptogenesis. Their antidepressant response involves the elevation of both extracellular glutamate and brain-derived neurotrophic factor (BDNF) levels, as well as the postsynaptic activation of the mammalian target of rapamycin complex 1. The mechanisms involved in the antidepressant outcomes of glutamatergic modulators, including ketamine, suggest that astrocytes must be considered a cellular target for developing rapid-acting antidepressants. It is well known that extracellular glutamate levels and glutamate intrasynaptic time-coursing are maintained by perisynaptic astrocytes, where inwardly rectifying potassium channels 4.1 (Kir4.1 channels) regulate both potassium and glutamate uptake. In addition, ketamine reduces membrane expression of Kir4.1 channels, which raises extracellular potassium and glutamate levels, increasing postsynaptic neural activities. Furthermore, inhibition of Kir4.1 channels stimulates BDNF expression in astrocytes, which may enhance synaptic connectivity. In this review, we discuss glutamatergic modulators' actions in regulating extracellular glutamate and BDNF levels, and reinforce the importance of perisynaptic astrocytes for the development of novel antidepressant drugs.