The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca(2+) channels

Neuron. 2010 Jul 15;67(1):116-28. doi: 10.1016/j.neuron.2010.05.030.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Analysis of Variance
  • Animals
  • CHO Cells
  • Calcium Channel Agonists / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / physiology*
  • Conditioning, Classical / drug effects
  • Cricetinae
  • Cricetulus
  • Drug Interactions
  • Electric Stimulation / methods
  • Fear / drug effects
  • Female
  • Hippocampus / cytology*
  • Hippocampus / physiology
  • Hyaluronic Acid / metabolism*
  • Hyaluronoglucosaminidase / pharmacology
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nifedipine / pharmacology
  • Patch-Clamp Techniques / methods
  • Synapses / physiology*
  • Transfection / methods


  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
  • Hyaluronic Acid
  • Hyaluronoglucosaminidase
  • Nifedipine