title: Heparan Sulfates Support Pyramidal Cell Excitability, Synaptic Plasticity, and Context Discrimination.
abstract: Heparan sulfate (HS) proteoglycans represent a major component of the extracellular matrix and are critical for brain development. However, their function in the mature brain remains to be characterized. Here, acute enzymatic digestion of HS side chains was used to uncover how HSs support hippocampal function in vitro and in vivo. We found that long-term potentiation (LTP) of synaptic transmission at CA3-CA1 Schaffer collateral synapses was impaired after removal of highly sulfated HSs with heparinase 1. This reduction was associated with decreased Ca2+ influx during LTP induction, which was the consequence of a reduced excitability of CA1 pyramidal neurons. At the subcellular level, heparinase treatment resulted in reorganization of the distal axon initial segment, as detected by a reduction in ankyrin G expression. In vivo, digestion of HSs impaired context discrimination in a fear conditioning paradigm and oscillatory network activity in the low theta band after fear conditioning. Thus, HSs maintain neuronal excitability and, as a consequence, support synaptic plasticity and learning.
authors.affiliation: Institute of Cellular Neurosciences, University of Bonn Medical School, 53105 Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Minge
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Senkov
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kaushik
authors.affiliation: Institute of Cellular Neurosciences, University of Bonn Medical School, 53105 Bonn, Germany.
authors.forename: Michel K
authors.initials: MK
authors.lastname: Herde
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.|Department of Neurotechnology, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Tikhobrazova
authors.affiliation: Institute of Cellular Neurosciences, University of Bonn Medical School, 53105 Bonn, Germany.
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Wulff
authors.affiliation: Department of Neurotechnology, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.|Central Research Laboratory, Nizhny Novgorod State Medical Academy, 603005 Nizhny Novgorod, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: Oosterhof
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.|Department of Molecular Pharmacology and Cell Biology, Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
authors.forename: Gaga
authors.initials: G
authors.lastname: Kochlamazashvili
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.|Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.|Department of Neurotechnology, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.|Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
authors.affiliation: Institute of Cellular Neurosciences, University of Bonn Medical School, 53105 Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.|Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Henneberger
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000096:biosynthesis / Q000235:genetics; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D003213:Conditioning, Psychological; D004192:Discrimination, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology; D019763:Heparin Lyase / Q000494:pharmacology; D006497:Heparan Sulfate / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013826:Theta Rhythm
chemical_list: D017487:Ankyrins; D019763:Heparin Lyase; D006497:Heparan Sulfate; C094681:Ank3 protein, mouse
keywords: extracellular matrix; heparan sulfates; learning; neuronal excitability; synaptic plasticity