title: BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.
abstract: Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression.
authors.affiliation: Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan;
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mizui
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, Nara 630-0192, Japan; Department of Systems Life Engineering Maebashi, Institute of Technology, Gunma 371-0816, Japan;
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan;
authors.forename: Haruko
authors.initials: H
authors.lastname: Kumanogoh
authors.affiliation: Institute of Biotechnology, University of Helsinki, FIN-00014, Helsinki, Finland;
authors.forename: Maria
authors.initials: M
authors.lastname: Lume
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Department of Psychiatry and Neurosciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan;
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hara
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Department of Psychiatry and Neurosciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan;
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamawaki
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Department of Biochemistry, Kitasato University School of Medicine, Kanagawa 228-8555, Japan;
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Laboratory of Functional Neuroscience, Nara Institute of Science and Technology, Nara 630-0192, Japan;
authors.forename: Sadao
authors.initials: S
authors.lastname: Shiosaka
authors.affiliation: Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan;
authors.forename: Chiaki
authors.initials: C
authors.lastname: Itami
authors.affiliation: Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Uegaki
authors.affiliation: Institute of Biotechnology, University of Helsinki, FIN-00014, Helsinki, Finland;
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.affiliation: Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan; Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan m-kojima@aist.go.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008715:Methionine / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D014633:Valine / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D008715:Methionine; D014633:Valine
keywords: growth factor; neuron; polymorphism; pro-peptide; synaptic plasticity