title: Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility.
abstract: BACKGROUND
  Guanine nucleotide exchange factors (GEFs) activate small GTPases that are involved in several cellular functions. cAMP-guanine nucleotide exchange factor II (cAMP-GEF II) acts as a target for cAMP independently of protein kinase A (PKA) and functions as a GEF for Rap1 and Rap2. Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive. Here, we investigated how cAMP-GEF II affects synaptic function and animal behavior using cAMP-GEF II knockout mice.
  
  
  RESULTS
  We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant. On the other hand, it produced a significant and clear impairment in NMDA receptor-dependent long-term depression at the Schaffer collateral-CA1 synapses of hippocampus, while microscopic morphology, basal synaptic transmission, and depotentiation were normal. Behavioral testing using the Morris water maze and automated IntelliCage system showed that cAMP-GEF II deficient mice had moderately reduced behavioral flexibility in spatial learning and memory.
  
  
  CONCLUSIONS
  We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.
authors.affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, 2-101, Dongin-dong, Jung-gu, Daegu, 700-842, Korea. irislkm@knu.ac.kr.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198, Japan. snow-k@brain.riken.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, 2-101, Dongin-dong, Jung-gu, Daegu, 700-842, Korea. hseo@knu.ac.kr.
authors.forename: Hyunhyo
authors.initials: H
authors.lastname: Seo
authors.affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, 2-101, Dongin-dong, Jung-gu, Daegu, 700-842, Korea. kwakd7415@naver.com.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198, Japan. masuda-akira@brain.riken.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-747, Korea. cslim@snu.ac.kr.
authors.forename: Chae-Seok
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-747, Korea. hrlee15@snu.ac.kr.
authors.forename: Hye-Ryeon
authors.initials: HR
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-746, Korea. sjkang24@snu.ac.kr.
authors.forename: SukJae Joshua
authors.initials: SJ
authors.lastname: Kang
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-746, Korea. pojeong@snu.ac.kr.
authors.forename: Pojeong
authors.initials: P
authors.lastname: Park
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-746, Korea. sesim@snu.ac.kr.
authors.forename: Su-Eon
authors.initials: SE
authors.lastname: Sim
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198, Japan. naomi_kogo@brain.riken.jp.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kogo
authors.affiliation: Department of Psychiatry, Faculty of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-Ku, Fukuoka, 814-0180, Japan. hkawasaki@fukuoka-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kawasaki
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-747, Korea. kaang@snu.ac.kr.|Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 151-746, Korea. kaang@snu.ac.kr.
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198, Japan. sitohara@brain.riken.jp.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D004597:Electroshock; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007858:Learning; D017774:Long-Term Potentiation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate