Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology

Abstract

SummaryAn increasing body of data has shown that matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn 2+ -dependent endopeptidase, is important not only for pathologies of the central nervous system but also for neuronal plasticity. Here, we use three independent experimental models to show that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal neurons. These models are: a recently developed transgenic rat overexpressing autoactivating MMP-9, dissociated neuronal cultures, and organotypic neuronal cultures treated with recombinant autoactivating MMP-9. This dendritic effect is mediated by integrin b1 signalling. MMP-9 treatment also produces a change in the decay time of miniature synaptic currents; however, it does not change the abundance and localization of synaptic markers in dendritic protrusions. Our results, considered together with several recent studies, strongly imply that MMP-9 is functionally involved in synaptic remodelling.

DP-b99 Modulates Matrix Metalloproteinase Activity and Neuronal Plasticity

“…Previous studies have shown that MMP-9 is involved in synaptic plasticity through influence on dendritic spine morphology, especially by provoking spine elongation [27]. Hence, we tested whether DP-b99 might reverse this effect in dissociated hippocampal cultures.…”

“…Therefore, we examined whether DP-b99 inhibits MMP-9 activity in vitro . We used a fluorometric gelatinolytic assay, in which recombinant MMP-9 as well as its known inhibitors (GM6001 and Inhibitor I) were employed (see also Michaluk et al [27]). Fig.…”

“…Hippocampal cultures from P0 Wistar rats were prepared as previously reported [27]. Cells were plated at a density of 100,000 cells per 18 mm diameter coverslip coated with 1 mg/ml poly-L-lysine (Sigma) and 2.5 µg/ml laminin (Roche).…”

Pharmacological modulation of brain activity in a preclinical model of osteoarthritis

“…In the case of a central nervous system diseased state, notably multiple sclerosis (Gijbels et al, 1992;Waubant et al, 1999) and brain ischemia (Romanic et al, 1998;Rosenberg et al, 1996), the activity of MMPs such as MMP-2, MMP-7 and MMP-9 is up-regulated. Preclinical models of drug dependence, Alzheimer's disease and epilepsy have shown involvement of MMP-2 and MMP-9 (Mizoguchi et al, 2011), while MMP-9 has been linked to normally occurring neuroplasticity that is not pathologic in nature (Michaluk et al, 2011). With respect to pain, Kawasaki and colleagues have recently demonstrated involvement of MMP-2 and MMP-9 in the spinal nerve ligation model (Ji et al, 2009;Kawasaki et al, 2008), a model of neuropathic pain.…”

A Glitch in the Matrix: Aberrant Extracellular Matrix Proteolysis Contributes to Alcohol Seeking

“…While MMP-9 is well established as both necessary and sufficient for long-term potentiation at hippocampal synapses, very little is known about its role in other brain sites, including the CeA (5). Previously, Michaluk et al (6) showed that rats that over-express an autoactive form of MMP-9 have greater numbers of long, thin spines, with no change in mushroom- or stubby-type spines in the hippocampus. Consistent with this finding, Stefaniuk et al (3) report a decrease in long, thin spines in MMP-9 KO mice, particularly in those that consumed the least amounts of ethanol, with no detected change in other spine subtypes.…”