Depression: A Novel Mechanism of Antidepressant Action with a Focus on Astrocytes

Postmortem studies of patients with depression show a reduction of glial cells and altered expression of glia-related genes in restricted areas of the brain, suggesting that glia are part of a neural network affected in the pathophysiology and treatment of the disorder. Glia, especially astrocytes, are major components in the CNS and play a role in the storage of several types of neurotrophic factors that might be systematically associated with the pathophysiology and treatment of depression. The expression of neurotrophic factors caused by antidepressants in glia is regulated by not only a monoamine-dependent, but also a monoamine-independent mechanism. Our data demonstrated that astrocytes stimulated by an antidepressant may be important mediators that produce several neurotrophic/growth factors, especially GDNF and FGF-2, through a de novo protein synthesis-dependent and a monoamine-independent mechanism. Antidepressants act directly on astrocytes to increase GDNF production after the activation of the FGFR/FRS2alpha/ERK/CREB signaling cascade via a MMPdependent shedding of FGFR ligands. Clarifying monoamine-independent novel targets of antidepressants in astrocytes may contribute to the development of more effective treatments for depression.

Keywords: Antidepressant, Astrocyte, Depression, Glia, Neurotrophic factor.