title: Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus.
abstract: Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3β/β-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice.
authors.affiliation: Department of Medicinal Biotechnology, College of Natural Resources and Life Science, Dong-A University, 37 Nakdong-Daero, 550 beon-gil, Saha-Gu, Busan 604-714, Republic of Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Science and Kyung Hee East-West Research Institute, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: H E
authors.initials: HE
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kwon
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Science and Kyung Hee East-West Research Institute, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Heo
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Science and Kyung Hee East-West Research Institute, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Republic of Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea. Electronic address: chanyshin@kku.ac.kr.
authors.forename: C Y
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Science and Kyung Hee East-West Research Institute, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-Gu, Seoul 130-701, Republic of Korea. Electronic address: jhryu63@khu.ac.kr.
authors.forename: J H
authors.initials: JH
authors.lastname: Ryu
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D049109:Cell Proliferation; D002560:Cerebrovascular Circulation / Q000502:physiology; D018891:Dentate Gyrus / Q000502:physiology*; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000473:pathology*; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D029681:Arabidopsis Proteins; D039481:CD11b Antigen; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C523534:TIC protein, Arabidopsis; D020032:Tyrphostins; D051176:beta Catenin; C447031:tyrphostin AG 1024; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine
keywords: IGF-1; glycogen synthase kinase-3β; immature neuron death; ischemia; microglia; neurogenesis