title: Upregulation of CREB-mediated transcription enhances both short- and long-term memory.
abstract: Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.
authors.affiliation: Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Suzuki
authors.forename: Hotaka
authors.initials: H
authors.lastname: Fukushima
authors.forename: Takuya
authors.initials: T
authors.lastname: Mukawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Yuze
authors.initials: Y
authors.lastname: Shang
authors.forename: Kengo
authors.initials: K
authors.lastname: Endoh
authors.forename: Taku
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Nori
authors.initials: N
authors.lastname: Mamiya
authors.forename: Emiko
authors.initials: E
authors.lastname: Okano
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Valentina
authors.initials: V
authors.lastname: Mercaldo
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ryouta
authors.initials: R
authors.lastname: Maeda
authors.forename: Miho
authors.initials: M
authors.lastname: Ohta
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kida
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D003214:Conditioning, Classical / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004192:Discrimination, Psychological; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005239:Fear; D031541:Fluorescence Resonance Energy Transfer; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D026121:Indole Alkaloids / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D018782:Maze Learning; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012919:Social Behavior; D014162:Transfection / Q000379:methods; D014443:Tyrosine / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D008164:Luminescent Proteins; D012333:RNA, Messenger; C054562:yellow fluorescent protein, Bacteria; D014443:Tyrosine; D010649:Phenylalanine; C049985:staurosporine aglycone; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse