Depression: A Novel Mechanism of Antidepressant Action with a Focus on Astrocytes
Pp. 220-232 (13)
Minoru Takebayashi, Kazue Hisaoka-Nakashima, Mami Okada- Tsuchioka, Chiyo Shibasaki, Hiromi Abe and Naoto Kajitani
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.
Antidepressant, Astrocyte, Depression, Glia, Neurotrophic factor.
Deptartment of Psychiatry, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama-cho, Kure 737-0023, Japan.