Fluoxetine : Neurogenesis : Depression

Fluoxetine-Induced Cortical Adult Neurogenesis

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Koji Ohira^1,2, Rika Takeuchi^1,2, Hirotaka Shoji^1,2 and Tsuyoshi Miyakawa^1,2,3

1. ¹Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan
2. ²Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan
3. ³Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan

Correspondence: Dr T Miyakawa or Dr K Ohira, Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan. E-mail:miyakawa@fujita-hu.ac.jp or ohira@fujita-hu.ac.jp

Received 12 July 2012; Revised 10 December 2012; Accepted 10 December 2012
Accepted article preview online 4 January 2013

The enhanced synapsin I promoter, WPRE, and Venus/pCS2 were gifts from Professor Kaneko (Kyoto University School of Medicine), Professor Hope (Northwestern University School of Medicine), and Dr Miyawaki (Brain Science Institute, Riken), respectively. This work was supported by the NEXT Program (LS-116) and CREST, JST.

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Abstract

Adult neurogenesis in the hippocampal subgranular zone (SGZ) and the anterior subventricular zone (SVZ) is regulated by multiple factors, including neurotransmitters, hormones, stress, aging, voluntary exercise, environmental enrichment, learning, and ischemia. Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) modulates adult neurogenesis in the SGZ, the neuronal area that is hypothesized to mediate the antidepressant effects of these substances. Layer 1 inhibitory neuron progenitor cells (L1-INP cells) were recently identified in the adult cortex, but it remains unclear what factors other than ischemia affect the neurogenesis of L1-INP cells. Here, we show that chronic treatment with an SSRI, fluoxetine (FLX), stimulated the neurogenesis of gamma-aminobutyric acid (GABA)ergic interneurons from L1-INP cells in the cortex of adult mice. Immunofluorescence and genetic analyses revealed that FLX treatment increased the number of L1-INP cells in all examined cortical regions in a dose-dependent manner. Furthermore, enhanced Venus reporter expression driven by the synapsin I promoter demonstrated that GABAergic interneurons were derived from retrovirally labeled L1-INP cells. In order to assess if these new GABAergic interneurons possess physiological function, we examined the their effect on apoptosis surrounding areas following ischemia. Intriguingly, the number of neurons expressing the apoptotic marker, active caspase-3, was significantly lower in adult mice pretreated with FLX. Our findings indicate that FLX stimulates the neurogenesis of cortical GABAergic interneurons, which might have, at least, some functions, including a suppressive effect on apoptosis induced by ischemia.

Keywords: 

adult neurogenesis; antidepressant; interneuron; neocortex; neural progenitor; stroke

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