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.

Synaptic circuit remodelling by matrix metalloproteinases in health and disease

“…These observations suggest that MMP9 contributes to a consolidation-like process during the first 30 min of LTP in which coordinated functional and structural plasticity becomes stable and immutable. Similar time-dependent effects of pharmacological MMP inhibitors on LTP persistence have been described for synapses in other hippocampal circuits 31 and in other brain regions, including the amygdala 5 and prefrontal cortex 32 .…”

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

“…In contrast, PPF (based on stimulus levels subthreshold for postsynaptic discharge, as used in the present study) has been assessed in fewer injury paradigms. It is notable that recent measurements in the intact hippocampal mossy fiber-CA3 projection, showed that MMP inhibition did not alter PPF, but did reduce LTP in the first minutes following HFS (Wojtowicz and Mozrzymas, 2010). While the importance of MMP mediation in Schaffer collateral PPF is controversial (Meighan et al, 2007;Nagy et al, 2006), our results suggest that in the complex TBI + BEC insult, MMPs have less influence on PPF short-term plasticity.…”

Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking

“…Matrix metalloproteinases are endopeptidases that degrade the extracellular matrix, and catalytic activation of the extracellular matrix by the gelatinase family of MMPs (MMP-2,9) is necessary for inducing hippocampal synaptic plasticity and facilitates hippocampus-dependent memory (18, 19). Activity of MMP-2,9 is also required for increasing AMPA:NMDA and spine dh during cue-induced t-SP in cocaine-trained rats (6).…”