title: proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus.
abstract: Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yang
authors.affiliation: The Nathan Kline Institute, Orangeburg, NY 10962, USA.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Harte-Hargrove
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Siao
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Marinic
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Roshelle
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.affiliation: The Nathan Kline Institute, Orangeburg, NY 10962, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lafrancois
authors.affiliation: Brown University, Providence, RI 02912, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Bath
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Willie
authors.initials: W
authors.lastname: Mark
authors.affiliation: Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Ballon
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: The Nathan Kline Institute, Orangeburg, NY 10962, USA; New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: hscharfman@nki.rfmh.org.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Scharfman
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: blhempst@med.cornell.edu.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
mesh_terms: D000483:Alleles; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*; D036881:Long-Term Synaptic Depression; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; C517634:Ngfr protein, mouse; D020813:Receptor, trkB
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