The extracellular matrix component hyaluronic acid supports hippocampal synaptic plasticity by modulating postsynaptic L-type Ca2+ channels.

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 element of the extracellular matrix. Enzymatic removal of HA with hyaluronidase reduced nifedipine-sensitive whole-cell Ca2+ currents and Ca2+ transients mediated by L-type voltage-dependent Ca2+ channels (L-VDCCs) in individual dendritic shafts and spines of CA1 pyramidal cells, and abolished an L-VDCC-dependent component of long-term potentiation (LTP) at the CA3-CA1 synapses. Adding exogenous HA, either by bath perfusion or via local delivery near to recorded synapses, completely rescued this LTP component. In a heterologous expression system, HA increased currents mediated by Cav1.2 but not Cav1.3 subunit-containing L-VDCCs. Injection of hyaluronidase in the brain impaired contextual fear conditioning. Our observations unveil a previously unrecognized mechanism by which the perisynaptic HA-rich extracellular matrix influences use-dependent synaptic plasticity through regulation of dendritic Ca2+ channels.