The antithetical effects of matrix metalloproteinase inhibition on hippocampal plasticity between young-adult and aged-adult rodents

Peter Conklin Meighan

doi:10.7273/000005608

It is becoming increasingly evident that matrix metalloproteinases (MMPs), a family of zinc containing extracellular endopeptidases, participate in processes supporting hippocampal synaptic plasticity. Specifically, we have recently demonstrated that hippocampal MMPs are upregulated during acquisition of a spatial memory task, and inhibition of hippocampal MMPs is deleterious to both task acquisition and long-term potentiation (LTP). The purpose of this study was twofold: (1) to further our understanding of MMPs importance in hippocampal plasticity and (2) to gain a mechanistic insight as to the functional importance of MMP activity for hippocampal plasticity. Acute hippocampal slices were generated from 20-30 day old male Sprague Dawley rats. Following recovery, control and MMP inhibitor (FN-439 Calbiochem) treated slices were subjected to various stimulatory paradigms which produce either short term or long term modifications to synaptic efficacy. Slices exposed to FN-439 exhibited impairments in paired pulse facilitation and theta burst facilitation; furthermore, FN-439 treated slices failed to stabilize following induction for LTP and long-term depression (LTD). Given the capability of MMPs to alter the extracellular and pericellular environment by degradation of extracellular matrix molecules and cell adhesion molecules, we hypothesized that the effects of FN-439 on LTP stabilization involves dysfunction to plasticity critical alterations to cell adhesion. To this end, we examined the temporal sensitivities of MMP inhibition by administering the inhibitor at various times following tetanization. Upon observing a similar temporal sensitivity pattern to that of integrin antagonist (GRGDSP Calbiochem), we predicted that FN-439 impacts LTP by interfering with integrin function. Consistent with this prediction, we observed that FN-439 competes for effect on LTP stabilization with the GRGDSP compound. Together, these data support a generalized role for MMPs for short term and long term hippocampal plasticity and that MMPs are a necessary facet of integrin mediated cell adhesion supporting LTP stabilization.; Results indicate that aged rats have markedly elevated levels of MMP-3 and that the ability to generate TBS induced LTP is limited. We hypothesized that excessive MMPs interferes with the normal remodeling processes that are requisite for the synaptic plasticity that accompanies learning and memory consolidation. To test this hypothesis, we first subjected hippocampal slices from aged-adult (20 months) Sprague-Dawley rats to a broad-spectrum MMP inhibitor prior to LTP testing. We observed that MMP inhibition enhanced LTP induction relative to untreated slices. This same treatment condition produced deficits in early-phase LTP maintenance in young-adult slices (3 months). Furthermore, we observed that exogenous application of catalytically active MMP-3 fragment to young-adult slices resulted in destabilization of LTP during early maintenance phase. These results suggest that age-related over-expression of hippocampal MMPs are deleterious to hippocampal plasticity.

The antithetical effects of matrix metalloproteinase inhibition on hippocampal plasticity between young-adult and aged-adult rodents

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