Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes
Manao Kinoshita,
Yuri Hirayama,
Kayoko Fujishita,
Keisuke Shibata,
Youichi Shinozaki,
Eiji Shigetomi,
Akiko Takeda,
Ha Pham Ngoc Le,
Hideaki Hayashi,
Miki Hiasa,
Yoshinori Moriyama,
Kazuhiro Ikenaka,
Kenji F. Tanaka,
Schuichi Koizumi
Affiliations
Manao Kinoshita
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Yuri Hirayama
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Kayoko Fujishita
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Keisuke Shibata
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Youichi Shinozaki
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Eiji Shigetomi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Akiko Takeda
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Ha Pham Ngoc Le
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Hideaki Hayashi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
Miki Hiasa
Department of Membrane Biochemistry, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
Yoshinori Moriyama
Department of Membrane Biochemistry, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; Department of Biochemistry, Matsumoto Dental University, Shiojiri 399-0781, Japan
Kazuhiro Ikenaka
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Kenji F. Tanaka
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan
Schuichi Koizumi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan; Corresponding author at: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission. Keywords: Astrocytes, Fluoxetine, ATP, Adenosine, Vesicular nucleotide transporter, BDNF
