title: Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus.
abstract: BACKGROUND
  Chronic treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) facilitates adult neurogenesis and reverses the state of maturation in mature granule cells (GCs) in the dentate gyrus (DG) of the hippocampus. Recent studies have suggested that the 5-HT4 receptor is involved in both effects. However, it is largely unknown how the 5-HT4 receptor mediates neurogenic effects in the DG and, how the neurogenic and dematuration effects of SSRIs interact with each other.
  
  
  RESULTS
  We addressed these issues using 5-HT4 receptor knockout (5-HT4R KO) mice. Expression of the 5-HT4 receptor was detected in mature GCs but not in neuronal progenitors of the DG. We found that chronic treatment with the SSRI fluoxetine significantly increased cell proliferation and the number of doublecortin-positive cells in the DG of wild-type mice, but not in 5-HT4R KO mice. We then examined the correlation between the increased neurogenesis and the dematuration of GCs. As reported previously, reduced expression of calbindin in the DG, as an index of dematuration, by chronic fluoxetine treatment was observed in wild-type mice but not in 5-HT4R KO mice. The proliferative effect of fluoxetine was inversely correlated with the expression level of calbindin in the DG. The expression of neurogenic factors in the DG, such as brain derived neurotrophic factor (Bdnf), was also associated with the progression of dematuration. These results indicate that the neurogenic effects of fluoxetine in the DG are closely associated with the progression of dematuration of GCs. In contrast, the DG in which neurogenesis was impaired by irradiation still showed significant reduction of calbindin expression by chronic fluoxetine treatment, suggesting that dematuration of GCs by fluoxetine does not require adult neurogenesis in the DG.
  
  
  CONCLUSIONS
  We demonstrated that the 5-HT4 receptor plays an important role in fluoxetine-induced adult neurogenesis in the DG in addition to GC dematuration, and that these phenomena are closely associated. Our results suggest that 5-HT4 receptor-mediated phenotypic changes, including dematuration in mature GCs, underlie the neurogenic effect of SSRIs in the DG, providing new insight into the cellular mechanisms of the neurogenic actions of SSRIs in the hippocampus.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. yukimo3116@gmail.com.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Imoto
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. cr.cr.cr.5.5@gmail.com.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kira
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. sukenomamiko@gmail.com.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sukeno
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. nishitani@mol.pharm.kyoto-u.ac.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Nishitani
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. nagayasu@mol.pharm.kyoto-u.ac.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nagayasu
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. tnakaga@pharm.kyoto-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. skaneko@pharm.kyoto-u.ac.jp.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan. kkatsu-tky@umin.ac.jp.|Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Saitama, 332-0012, Japan. kkatsu-tky@umin.ac.jp.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan. eri.segi.nishida@rs.tus.ac.jp.
authors.forename: Eri
authors.initials: E
authors.lastname: Segi-Nishida
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D018891:Dentate Gyrus / Q000166:cytology*; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D055495:Neurogenesis / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014965:X-Rays
chemical_list: D005473:Fluoxetine; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin