Antidepressant Administration Modulates Neural Stem Cell Survival and Serotoninergic Differentiation Through Bcl-2

Shih-Jen      Chen; Chun-Lan      Kao; Yuh-Lih      Chang; Chih-Ju      Yen; Jia-Wei      Shui; Chan-Shiu      Chien; I-Lin      Chen; Tung-Hu      Tsai; Hung-Hai      Ku; Shih-Hwa      Chiou

doi:10.2174/156720207779940707

Abstract

The hippocampus has long been associated with learning, memory, and modulation of emotional responses. Previous studies demonstrated that stress-induced loss of hippocampal neurons may contribute to the pathogenesis of depression. The recent observations supported that antidepressant drugs increase the production of serotoninergic neurotransmitter and they play a critical role in the initiation of neurogenesis in the hippocampus. In order to explore the possible new mechanism of the treatment of depression, we cultured neural stem cells (NSCs) derived from the hippocampus of adult rats as an in vitro model to evaluate the capabilities of neuroprotection and neural differentiation in NSCs by fluoxetine (FL) treatment. Our results showed that 20 μM FL treatment can significantly increase the proliferation rate of NSCs (p < 0.05), and up-regulate the mRNA and protein expressions of Bcl-2 in Day-7 FL-treated NSCs (p < 0.01). Using Bcl-2 gene silencing with small interfering RNA, our data verified that FL can prevent Fas ligand-induced caspasedependent apoptosis in NSCs through the activation of Bcl-2. The in vitro observation and immunofluorescent study further demonstrated that FL treatment can stimulate the neurite development and serotoninergic differentiation of NSCs through the activation of Bcl-2. Using microdialysis with high performance liquid chromatography- electrochemical detection, the functional release of serotonin in the differentiating NSCs with FL treatment was increased and simultaneously regulated by the Bcl-2 expressions. In sum, the study results indicate that antidepressant administration can increase NSCs survival, promote the neurite development, and facilitate NSCs differentiating into the functional serotoninergic neurons via the modulation of Bcl-2 expression.

Keywords: Hippocampus, antidepressant drug, fluoxetine, neurogenesis, neuroprotection, neural stem cells, serotonin, Bcl-2