Abstract
We examined the role of astrocytes in the molecular pathogenesis of depression based on the pharmacological effects of the SSRI‐type antidepressants fluoxetine (FLX) and ketamine on glial cells, especially astrocytes. In addition to inhibition of serotonin uptake, chronic administration of FLX had a role to enhance astrocytic ATP exocytosis and ATP receptor‐dependent BDNF production, resulting in antidepressant effects. On the other hand, ketamine, well‐known as a general anesthetic by inhibition of NMDA receptors, showed immediate and sustained antidepressant effects at concentrations lower than the anesthetic dose. The ketamine‐hypersensitive NMDA receptors are astrocyte‐specific, and ketamine produced immediate and sustained antidepressant effects by altering the plasticity of astrocytes through these receptors. Although they are completely different antidepressants, they share some common mechanisms of action by acting on astrocytes to normalize the neuro‐glial coupling. These results suggest that astrocytes may be a promising therapeutic target for depression.
