title: EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation.
abstract: EPAC proteins are the guanine nucleotide exchange factors that act as the intracellular receptors for cyclic AMP. Two variants of EPAC genes including EPAC1 and EPAC2 are cloned and are widely expressed throughout the brain. But, their functions in the brain remain unknown. Here, we genetically delete EPAC1 (EPAC1(-/-)), EPAC2 (EPAC2(-/-)), or both EPAC1 and EPAC2 genes (EPAC(-/-)) in the forebrain of mice. We show that EPAC null mutation impairs long-term potentiation (LTP) and that this impairment is paralleled with the severe deficits in spatial learning and social interactions and is mediated in a direct manner by miR-124 transcription and Zif268 translation. Knockdown of miR-124 restores Zif268 and hence reverses all aspects of the EPAC(-/-) phenotypes, whereas expression of miR-124 or knockdown of Zif268 reproduces the effects of EPAC null mutation. Thus, EPAC proteins control miR-124 transcription in the brain for processing spatial learning and social interactions.
authors.affiliation: Key Laboratory of Neurological Disease, Ministry of Education, China, and Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Shu
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: You
authors.initials: Y
authors.lastname: Shang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Pei
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.forename: Ya-Xian
authors.initials: YX
authors.lastname: Wang
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: Weihong
authors.initials: W
authors.lastname: Tu
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D047369:Chromatin Immunoprecipitation; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D005106:Exploratory Behavior / Q000502:physiology; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency*; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D066298:In Vitro Techniques; D007398:Interpersonal Relations; D007859:Learning Disabilities / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D009474:Neurons / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D018408:Patch-Clamp Techniques; D014176:Protein Biosynthesis / Q000235:genetics; D011930:Reaction Time / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D016622:Silver Staining; D014162:Transfection; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; C486707:Rapgef4 protein, mouse; D020827:rap1 GTP-Binding Proteins