Late phase of long‐term potentiation in the mossy fiber—CA3 hippocampal pathway is critically dependent on metalloproteinases activity

Abstract

Matrix metalloproteinases (MMPs) are known to play a pivotal role in remodeling of the extracellular matrix and have been implicated in synaptic plasticity, learning and memory. In hippocampus, inhibition of MMPs impairs the maintenance of long term plasticity in Schaeffer collateral-CA1 (Sch/CA1) synapses while its effect on short term plasticity remains a matter of debate. Surprisingly little is known on the role of MMPs in other hippocampal synapses. In this study we have investigated the impact of a broad spectrum MMPs inhibitor, FN-439 on synaptic transmission in mossy fiber-CA3 (MF/CA3) synapses exhibiting profoundly different mechanism of long term potentiation (LTP) as well as robust short-term plasticity, features that clearly distinguish them from the Sch/CA1 synapses. We report, that MMPs blockade before and up to 30 minutes after LTP induction resulted in a severe disruption of the late phase of tetanically induced LTP. However, LTP time course was not changed when FN439 was administered 60 minutes post LTP induction indicating that MMPs activity is required for the consolidation of the synaptic plasticity within a specific time window. The paired-pulse facilitation ratio or post-tetanic potentiation or burst-like pattern of mossy fiber stimulation were not changed in the presence of FN-439 administered for 15 minutes suggesting that temporal pattern of presynaptic transmitter release and, in general, the MF-CA3 fidelity is not significantly affected by MMPs inhibition. We conclude that although the mechanisms of long-term plasticity in MF/CA3 and in Sch/CA1 are profoundly different, MMPs play a crucial role in both pathways in the maintenance of LTP, which is believed to play an important role in learning and memory in the hippocampus.