title: The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca(2+) channels.
abstract: Although the extracellular matrix plays an important role in regulating use-dependent synaptic plasticity, the underlying molecular mechanisms are poorly understood. Here we examined the synaptic function of hyaluronic acid (HA), a major component of the extracellular matrix. Enzymatic removal of HA with hyaluronidase reduced nifedipine-sensitive whole-cell Ca(2+) currents, decreased Ca(2+) transients mediated by L-type voltage-dependent Ca(2+) channels (L-VDCCs) in postsynaptic dendritic shafts and spines, and abolished an L-VDCC-dependent component of long-term potentiation (LTP) at the CA3-CA1 synapses in the hippocampus. Adding exogenous HA, either by bath perfusion or via local delivery near recorded synapses, completely rescued this LTP component. In a heterologous expression system, exogenous HA rapidly increased currents mediated by Ca(v)1.2, but not Ca(v)1.3, subunit-containing L-VDCCs, whereas intrahippocampal injection of hyaluronidase impaired contextual fear conditioning. Our observations unveil a previously unrecognized mechanism by which the perisynaptic extracellular matrix influences use-dependent synaptic plasticity through regulation of dendritic Ca(2+) channels.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 85, Hamburg, Germany.
authors.forename: Gaga
authors.initials: G
authors.lastname: Kochlamazashvili
authors.forename: Christian
authors.initials: C
authors.lastname: Henneberger
authors.forename: Olena
authors.initials: O
authors.lastname: Bukalo
authors.forename: Elena
authors.initials: E
authors.lastname: Dvoretskova
authors.forename: Oleg
authors.initials: O
authors.lastname: Senkov
authors.forename: Patricia M-J
authors.initials: PM
authors.lastname: Lievens
authors.forename: Ruth
authors.initials: R
authors.lastname: Westenbroek
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Engel
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Rusakov
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D003214:Conditioning, Classical / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005239:Fear / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D013569:Synapses / Q000502:physiology*; D014162:Transfection / Q000379:methods
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D009543:Nifedipine