title: Drp1-mediated mitochondrial abnormalities link to synaptic injury in diabetes model.
abstract: Diabetes has adverse effects on the brain, especially the hippocampus, which is particularly susceptible to synaptic injury and cognitive dysfunction. The underlying mechanisms and strategies to rescue such injury and dysfunction are not well understood. Using a mouse model of type 2 diabetes (db/db mice) and a human neuronal cell line treated with high concentration of glucose, we demonstrate aberrant mitochondrial morphology, reduced ATP production, and impaired activity of complex I. These mitochondrial abnormalities are induced by imbalanced mitochondrial fusion and fission via a glycogen synthase kinase 3β (GSK3β)/dynamin-related protein-1 (Drp1)-dependent mechanism. Modulation of the Drp1 pathway or inhibition of GSK3β activity restores hippocampal long-term potentiation that is impaired in db/db mice. Our results point to a novel role for mitochondria in diabetes-induced synaptic impairment. Exploration of the mechanisms behind diabetes-induced synaptic deficit may provide a novel treatment for mitochondrial and synaptic injury in patients with diabetes.
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Shengbin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Xueqi
authors.initials: X
authors.lastname: Gan
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Du
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Changjia
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Sosunov
authors.affiliation: Department of Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Guy M
authors.initials: GM
authors.lastname: McKhann
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pharmacology & Toxicology and Higuchi Biosciences Center, School of Pharmacy, University of Kansas, Lawrence, KS shidu@ku.edu.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000818:Animals; D002460:Cell Line; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C486391:Dnm1l protein, mouse; D034281:Dynamins