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MMP9: A novel function in synaptic plasticity
The International Journal of Biochemistry & Cell Biology 44 (2012) 709–713
Contents lists available at SciVerse ScienceDirect
The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel
Molecules in focus
MMP9: A novel function in synaptic plasticity Magdalena Dziembowska, Jakub Wlodarczyk ∗ Nencki Institute, 02-093 Warsaw, Pasteura 3, Poland
a r t i c l e
i n f o
Article history: Received 12 December 2011 Received in revised form 28 January 2012 Accepted 31 January 2012 Available online 9 February 2012 Keywords: Brain Matrix metalloproteinase-9 Dendritic spine morphology Synaptic plasticity Memory and learning processes
a b s t r a c t Matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn2+ -dependent endopeptidase is a subject to complex regulation at the level of transcription, mRNA dendritic translocation, and local translation as well as protein activation, as it is released extracellularly in a latent, pro-form with the enzymatic site covered by a propeptide that has to be cleaved off to reveal the activity. In neurons, MMP-9 is present at the postsynaptic domains of excitatory synapses. Here, we review the role of MMP-9 in induction of structural dendritic spine modifications and in synaptic plasticity. In particular, we focus on local translation, activity-dependent secretion and activation of MMP-9 leading to its role in long term potentiation and regulation of remodeling of dendritic spines. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction The matrix metalloproteinases (MMPs) are a family of zincdependent enzymes which operate extracellularly and are able to degrade components of the extracellular matrix ECM (Woessner, 1991).
matrix metalloproteinases-1 (TIMP-1) to proMMP-9 (Olson et al., 1997), while three tandem repeats of fibronectin type II modules are responsible for gelatin binding. The flexible and unstructured linker domain is implicated in independent movements of the terminal domains and in varied enzyme conformations (Rosenblum et al., 2007).
2. Structure
3. Expression and activation in neurons
The primary structure of MMP-9 (gelatinase B) (EC 3.4.24.25) starting from N-terminus is composed of the following domains: a signal peptide, a propeptide, a catalytic domain that may bind a zinc ion, a three tandem repeats of fibronectin type II inserts within the catalytic domain, a proline-rich and heavily O-glycosylated linker, and a hemopexin-like domain (Stute et al., 2003) (Fig. 1). The propeptide domain contains conserved PRCGVPDV motive that binds to the zinc ion of the catalytic center via the cysteine residue in order to maintain the latency of the proenzyme (Van Wart and Birkedal-Hansen, 1990; Becker et al., 1995). The enzyme activation occurs by the propeptide cleavage that is responsible for disruption of cysteine-zinc ion interaction. The catalytic domain of MMP-9 contains, zinc-binding motif HExGHxxGxxH (where x states for any amino acids) highly conserved in all MMPs and responsible for overlapping its substrate specificity with other MMPs. A hemopexin-like domain at the carboxyl terminus of MMP9 is reported to be required for the binding of tissue inhibitor of
MMP-9 is an important enzyme involved in matrix remodeling during the normal processes of embryogenesis, tissue remodeling and development. In addition to its role in maintaining tissue homeostasis MMP-9 was shown to be activated in such pathologies as cancer (it modulates tumor micro-environment and enhances metastasis) or in acute and chronic neurological conditions e.g. stroke or multiple sclerosis (Kessenbrock et al., 2010; Yong et al., 2005). Recently, MMP-9 has also emerged as a novel regulator of physiological processes in healthy adult CNS, such as synaptic plasticity, learning and memory (Rivera et al., 2010) (Fig. 2). Matrix metalloproteinase-9 is expressed in such adult brain structures as hippocampus, cerebral cortex and cerebellum. It is mostly produced by neurons, but to some extent also by glia. In neurons, MMP-9 expression is induced by neuronal activity under physiological as well as pathological conditions such as epilepsy or stroke. Aberrant, and usually excessive MMP-9 gene expression has been linked to numerous disorders of the central nervous system (Dzwonek et al., 2004). The regulation of Mmp-9 gene promoter has been extensively studied in non-neuronal cells. In neurons, the most prominent transcription factors implicated in Mmp-9 gene activation are AP-1 and
∗ Corresponding author. Tel.: +48 22 589 2360. E-mail address: [email protected] (J. Wlodarczyk). 1357-2725/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2012.01.023
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M. Dziembowska, J. Wlodarczyk / The International Journal of Biochemistry & Cell Biology 44 (2012) 709–713
and then it is activated by proteolytic cleavage. It was demonstrated that neuronal stimulation releases the required inactive proMMP9, which is activated extracellularly. A number of proteases seem to be involved in cleaving off the propeptide, including MMPs themselves and, in particular, components of the plasminogen–plasmin system (Bruno and Cuello, 2006). Plasminogen conversion to plasmin activated by either tissue plasminogen activator or urokinase plasminogen activator plays a role in activation of proteolytic system composed of MMP-9 and its endogenous inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinases) (Dzwonek et al., 2004). MMP-9 is directly regulated by TIMP-1 but also by glycosylation and internalization (Yong, 2005). It should be emphasized that the MMPs are active very locally, at the sites of release, as well as very transiently, being rapidly inhibited by, probably co-released, TIMPs. Michaluk et al. (2007) have shown increased MMP-9 activity within 5 min after synaptic stimulation. Sbai et al. (2008) have shown that MMPs and TIMP-1 are secreted in 160–200 nm vesicles in a Golgi-dependent pathway. These vesicles distribute along microtubules and microfilaments, colocalise differentially with the molecular motors kinesin and myosin Va and undergo both anterograde and retrograde trafficking. MMP-9 vesicles are preferentially distributed in the somato-dendritic compartment and are found in dendritic spines (Sbai et al., 2008). It was also shown that in human fibrosarcoma cell line HT-1080 that MMP-9 release can occur via a SNARE (soluble NSF attachment protein receptor) dependent mechanism (Kean et al., 2009). In neurons such mechanism of MMP-9 secretion have not been described. Once secreted and activated MMP-9 causes the proteolytic degradation of its extracellular substrates e.g. proteins such as beta-dystroglycan, N-cadherin, membrane-bound receptors e.g. 1 containing integrins but also neurotrophins, such as brain derived neurotrofic factor (BDNF) or nerve growth factor (NGF). Probably, there are more physiological targets of the MMP-9 that need to be identified to fully understand its function at the synapse. It has been shown that activity-dependent substrate cleavage by synaptic metalloproteases and ␥-secretase decreases levels of synaptic proteins and diminishes synaptic transmission (Restituito et al., 2011). Fig. 1. Domain structure (left) and ternary structure (right) of MMP-9, composed of: a signal peptide (white), a propeptide (green), a catalytic domain (red) that contains a zinc ion (grey), a three tandem repeats of fibronectin type II inserts (blue) within the catalytic domain, a proline-rich and heavily O-glycosylated linker (dashed line), and a hemopexin-like domain (grey).
NF-B. In the promoter region of Mmp-9 gene, spanning about 1000 bp, three functional AP-1 and one NF-B binding site have been identified. The transcriptional regulator Yin Yang 1 (YY1) was shown to act as a strong repressor of Mmp-9 transcription in the rat hippocampus in vivo, as well as in the cultured neurons. Synaptic stimulation leads to YY1 dissociation from MMP-9 proximal promoter and activation of the gene expression (Rylski et al., 2008). Recently we have discovered an additional level of MMP-9 regulation in neurons, e.g. its local translation in synapto-dendritic compartment (Dziembowska et al., submitted for publication). MMP-9 mRNA is transported to the dendrites and locally translated upon synaptic stimulation in hippocampal neurons, and by LTP induced in the hippocampal dentate gyrus by high-frequency stimulation (HFS) of the medial perforant path in the rat brain. This data are consistent with previous studies showing MMP-9 mRNA and the protein to be present at the postsynaptic domains of glutamatergic synapses, e.g. at the dendritic spines (Konopacki et al., 2007; Gawlak et al., 2009; Wilczynski et al., 2008). Moreover, the enzymatic activity of MMP-9 was demonstrated at the synapses (Gawlak et al., 2009). MMP-9 is produced at the synapse and released into the extracellular space in an activity-dependent manner in a precursor form,
4. Role in synaptic plasticity The synaptic plasticity may be defined as a re-organization of the synaptic connections that comprises both, alterations at the morphological level and changes at the functional level. Enhanced neuronal activity and some aspects of plasticity are mimicked by experimental paradigms such as long-term potentiation (LTP). Recent studies indicate that spine structure can be regulated by extracellular matrix (ECM). Notably, an involvement of MMP9 in modulation of morphology of the dendritic spines has been reported. Release of MMP-9 and its local activity, in response to stimuli that produce enhancement of neuronal responses have been shown to affect spine morphology (Wang et al., 2008; Bilousova et al., 2009). Wang et al. (2008) reported that in acute hippocampal slices MMP-9 was necessary for enlargement of spines associated with long-term potentiation (LTP) induction. MMP-9 influence on dendritic spine enlargement and LTP coordinately implicates its instructive role in establishing persistent modifications in both synapse structure and function (Wang et al., 2008). Furthermore, Tian et al. (2007) have found that MMP-9, via cleavage of the intercellular adhesion molecule-5 (ICAM-5), can also cause elongation of dendritic filopodia in dissociated neuronal cultures. We have recently reported (Michaluk et al., 2011) using three independent experimental models (transgenic rat overexpressing autoactivating MMP-9, dissociated hippocampal cultures, and organotypic cultures) that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal
M. Dziembowska, J. Wlodarczyk / The International Journal of Biochemistry & Cell Biology 44 (2012) 709–713
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Fig. 2. MMP-9 is locally released at the dendritic spines in a non-active form. The propeptide which block the enzymatic active site is cleaved off by a cascade of extracellular proteases, involving e.g. tPA-plasmin-plasminogen system. Once activated, MMP-9 cleaves ECM/CAMs, such as dystroglycan. The cleavage products act on integrin receptors to transduce the signals provoking actin cytoskeleton modifications underlying the growth of spines.
neurons. This dendritic effect was shown to be mediated by integrin 1 signaling and accompanied by changes in the decay time of miniature synaptic currents. Notably, MMP-9 increases lateral dendritic mobility of NMDAR and this effect as well as MMP-9 ability to affect spine morphology are abolished by the integrin 1 blocking antibody. Similarly, an incubation of dissociated neuronal culture with recombinant MMP-9 caused transformation of dendritic spines from mushroom- to filopodia-like protrusions (Bilousova et al., 2009). Notably, Bilousova et al. (2009) showed that in the fragile X mouse model (Fmr1 KO mice) an increase in proportion of filopodia to mature spines could be reversed by minocycline, whose pleiotropic effects include the ability to inhibit MMP-9. MMP-9 dependent changes in dendritic spine morphology appear to involve -dystroglycan, ICAM-5 and integrins, especially integrin 1 molecules (Nagy et al., 2006; Michaluk et al., 2007; Tian et al., 2007; Michaluk et al., 2009; Conant et al., 2010). The above findings apparently indicate on divergent effect of MMP-9 on spine morphology and raise the question regarding the factors playing the role in seemingly contradictory effects. Differences in MMP-9 dose (local vs. bath application), time-frames of enhanced MMP-9 activity associated with subsequent inhibitory effect by endogenous MMP-9 inhibitor, and the maturity of neurons used in the studied system appear to be involved. While the Wang et al. (2008) reported that MMP-9 promoted the maturation of dendritic spines, the others have instead shown that MMP-9 (Michaluk et al., 2011) or MMP-9 released products (Tian et al., 2007) can stimulate spine elongation. However, the authors have used a different brain slice models i.e. acute slices from P14 to P21 rats (Wang et al., 2008) vs. organotypic culture from P7 rats kept 11 DIV implemented by Michaluk et al. (2011). Furthermore, Wang et al. (2008) applied MMP-9 locally via a stimulating electrode, instead Michaluk et al. (2011) used bath application. The
local application might resemble physiological conditions more closely, since MMPs are thought to act both locally and transiently, as their activity is very strictly controlled. In contrast, the bath application resembles much more of a pathological situation when MMP-9 activity is out of control and would explain the mechanism of spine morphological changes during either stroke or epilepsy (Wilczynski et al., 2008). Similarly, Tian et al. (2007) used a fairly high dose of soluble ICAM-5 (for 72 h on 9 DIV neurons) and found that this treatment promote elongation of spines in a manner that was dependent on the presence of cell surface ICAM-5 mainly located on immature spines. This suggests that more mature neurons, which may express less surface ICAM-5 in comparison to immature spines, might respond differently. Additionally, the data on the effect MMP-9 inhibition on spine morphology (Bilousova et al., 2009; Tian et al., 2007; as well as our unpublished data) appear to suggest that the inhibition of MMP-9 may conclude the process of spine elongation and promotes the transformation of dendritic spines toward mature, mushroom shaped spines. Several recent reports have also demonstrated an importance of MMP-9 and its pivotal functional role in physiological long term potentiation (LTP) (see Wlodarczyk et al., 2011 for review) at diverse brain regions. Nagy et al. (2006) have provided evidence that both MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late phase of LTP (L-LTP). Moreover, the same authors demonstrated the impairment of CA3-CA1 L-LTP in slices, using MMP-9 knock-out mice as well as broad spectrum chemical inhibitors directed against MMPs. Simultaneously, Meighan et al. (2006) have shown that the inhibition of MMP-9 expression by the use of MMP-9 antisense oligonucleotides and activity (by the use of chemical inhibitors) altered the maintenance but not the induction of L-LTP. Functional role of MMP-9 in CA1 L-LTP has been also shown in vivo, by means of application
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of chemical inhibitors and neutralizing antibodies (Bozdagi et al., 2007). Similarly, Okulski et al. (2007) reported that blocking MMP-9 either by specific chemical inhibitor or by overexpression of TIMP1 impaired L-LTP (but not the induction of LTP) in the subiculum to prefrontal cortex pathway in freely moving rats as well as in the cortical slices. A role for MMPs, by means of application of a broad spectrum inhibitor, has also been revealed for the mossy fiber LTP in the hippocampus (Wojtowicz and Mozrzymas, 2010). In addition to the role of MMP-9 in physiological plasticity, various pathological conditions subserved by abnormal synaptic plasticity have been implied to involve MMP-9, e.g. epileptogenesis. The first data indicating the role of MMP/TIMP system in aberrant synaptic plasticity were provided by Nedivi et al. (1993) who have shown TIMP-1 mRNA up-regulation within the dentate gyrus (DG) after KA induced seizures. Szklarczyk et al. (2002) demonstrated that not only TIMP-1 gene expression but also MMP-9 expression (both at the level of mRNA, protein and enzymatic activity) was upregulated in DG following KA seizure. Furthermore, Wilczynski et al. (2008) demonstrated that MMP-9 is localized to excitatory synapses, where upon epileptic seizure both the MMP-9 protein level and enzymatic activity become strongly elevated. The same authors using two animal models of epileptogenesis, i.e. KA-evoked epilepsy and PTZ kindling demonstrated that the sensitivity to PTZ kindling was elevated in transgenic rats overexpressing MMP-9 and decreased in MMP-9 knockout mice. These finding were supported by several lines of evidence indicating increased synaptic accumulation of MMP-9 mRNA and neuronal MMP-9 levels following seizures (Konopacki et al., 2007; Michaluk et al., 2007; Gawlak et al., 2009; Rylski et al., 2008). A functional role of MMP-9 in the development of epilepsy has been supported by more recent studies (see Lukasiuk et al., 2011 for review and citations therein). MMP-9 plays also a functional role in various forms of synaptic plasticity characterized by drug addiction (see Rivera et al., 2010 for review). Brown et al. (2007), using intracerebral ventricular injection of a broad-spectrum MMP inhibitor prior to cocaine training, have shown that MMPs play a critical role in acquisition and reconsolidation of cocaine-induced place preference. Moreover the same authors (Brown et al., 2007) have shown that rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement. Furthermore, in MMP-9 KO mice diminished behavioral response to methamphetamine (MA) addictive treatment was reported (Mizoguchi et al., 2007). Additionally, mutant mice exhibited resistance to the inhibitory effect of treatment on dopamine transport activity (Mizoguchi et al., 2007). In vivo administration of acute dose of MA causes an increase in MMP-9 protein that occurs within 6 h in murine hippocampus and striatum. This is associated with MMP dependent cleavage of ICAM-5. The shedding ICAM-5 ectodomain that interacts with (1) integrin leads to increase in the phosphorylation of cofilin, an event permissive for spine expansion (Conant et al., 2011). It has also been reported that ethanol-induced impairment of watermaze learning correlated with reduced hippocampal and prefrontal cortex MMP-9 activity (Wright et al., 2003). More recently, it has been shown that MMP-9 in the spinal cord also contributes to development of physical dependence on morphine in mice (Liu et al., 2010).
5. Conclusions Matrix metaloproteinase-9 undergoes very complex regulation; it is secreted and activated in the extracellular space in response to enhanced neuronal activity. This enzyme can cleave and release signaling molecules from CAMs, which may affect morphology of existing dendritic spines. This effect is most probably mediated by integrin dependent signaling. Pivotal role of MMP-9 in the synaptic
plasticity at the level of gene expression, changes in dendritic spine morphology and synaptic transmission has been documented. Sustained increase in neuronal MMP-9 level has shown to contribute to the aberrant plasticity underlying neuronal pathologies such as epileptogenesis. In conclusion, the extracellular matrix (ECM) has been recently recognized as a critical factor affecting synapses, as it is forming integral synaptic component in addition to pre- and post-synapse, as well as glial invaginations. Although the role of ECM molecules such as MMP-9 in synaptic plasticity has recently started to be acknowledged, the questions regarding the exact nature of molecular events taking part in those phenomena, remains open. The ability of MMP-9, the ECM modifier, to release signaling molecules from the ECM has drawn recently considerable attention and stimulate further interest to better understanding of subcellular localization of active MMP-9, role of non-active proteinase as well as signaling transduction pathways. These data, together with the beneficial effects of MMP-9 on synaptic plasticity argue in a favor of multifaceted view on the role of the MMP-9 on synaptic plasticity and may eventually open a novel approaches for the development of new tools and adequate treatments for neurodegenerative disorders and drug addiction. Acknowledgments J.W. was supported by ERA-NET NEURON MODDIFSYN. M.D. was supported by grant from Polish Ministry of Science and Higher Education no. N N301 033134. This work was supported by the COST Action BM1001 “Brain Extracellular Matrix in Health and Disease”. We thank Prof L. Kaczmarek and Prof G.M. Wilczynski for valuable discussions and suggestions regarding the manuscripts. References Becker JW, Marcy AI, Rokosz LL, Axel MG, Burbaum JJ, Fitzgerald PM, et al. Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci 1995;4:1966–76. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 2009;46:94–102. Bozdagi O, Nagy V, Kwei KT, Huntley GW. In vivo roles for matrix metalloproteinase9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol 2007;98:334–44. Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci U S A 2006;103:6735–40. Brown TE, Forquer MR, Cocking DL, Jansen HT, Harding JW, Sorg BA. Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference. Learn Mem 2007;14:214–23. Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, Lim ST. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 2010;166:508–21. Conant K, Lonskaya I, Szklarczyk A, Krall C, Steiner J, Maguire-Zeiss K, et al. Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5. J Neurochem 2011;118:521–32. Dziembowska M, Milek J, Janusz A, Rejmak E, Romanowska E, Tiron A, Bramham C, Kaczmarek L. MMP-9 is locally translated in neurons. submitted for publication. Dzwonek J, Rylski M, Kaczmarek L. Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in neuronal physiology of the adult brain. FEBS Lett 2004;567:129–35. Gawlak M, Gorkiewicz T, Gorlewicz A, Konopacki FA, Kaczmarek L, Wilczynski GM. High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses. Neuroscience 2009;158:167–76. Kean MJ, Williams KC, Skalski M, Myers D, Burtnik A, Foster D, et al. VAMP3, syntaxin-13 and SNAP23 are involved in secretion of matrix metalloproteinases, degradation of the extracellular matrix and cell invasion. J Cell Sci 2009;122:4089–98. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141:52–67. Konopacki FA, Rylski M, Wilczek E, Amborska R, Detka D, Kaczmarek L, et al. Synaptic localization of seizure-induced matrix metalloproteinase-9 mRNA. Neuroscience 2007;150:31–9. Liu WT, Han Y, Liu YP, Song AA, Barnes B, Song XJ. Spinal matrix metalloproteinase9 contributes to physical dependence on morphine in mice. J Neurosci 2010;30:7613–23.
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Contents lists available at SciVerse ScienceDirect
The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel
Molecules in focus
MMP9: A novel function in synaptic plasticity Magdalena Dziembowska, Jakub Wlodarczyk ∗ Nencki Institute, 02-093 Warsaw, Pasteura 3, Poland
a r t i c l e
i n f o
Article history: Received 12 December 2011 Received in revised form 28 January 2012 Accepted 31 January 2012 Available online 9 February 2012 Keywords: Brain Matrix metalloproteinase-9 Dendritic spine morphology Synaptic plasticity Memory and learning processes
a b s t r a c t Matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn2+ -dependent endopeptidase is a subject to complex regulation at the level of transcription, mRNA dendritic translocation, and local translation as well as protein activation, as it is released extracellularly in a latent, pro-form with the enzymatic site covered by a propeptide that has to be cleaved off to reveal the activity. In neurons, MMP-9 is present at the postsynaptic domains of excitatory synapses. Here, we review the role of MMP-9 in induction of structural dendritic spine modifications and in synaptic plasticity. In particular, we focus on local translation, activity-dependent secretion and activation of MMP-9 leading to its role in long term potentiation and regulation of remodeling of dendritic spines. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction The matrix metalloproteinases (MMPs) are a family of zincdependent enzymes which operate extracellularly and are able to degrade components of the extracellular matrix ECM (Woessner, 1991).
matrix metalloproteinases-1 (TIMP-1) to proMMP-9 (Olson et al., 1997), while three tandem repeats of fibronectin type II modules are responsible for gelatin binding. The flexible and unstructured linker domain is implicated in independent movements of the terminal domains and in varied enzyme conformations (Rosenblum et al., 2007).
2. Structure
3. Expression and activation in neurons
The primary structure of MMP-9 (gelatinase B) (EC 3.4.24.25) starting from N-terminus is composed of the following domains: a signal peptide, a propeptide, a catalytic domain that may bind a zinc ion, a three tandem repeats of fibronectin type II inserts within the catalytic domain, a proline-rich and heavily O-glycosylated linker, and a hemopexin-like domain (Stute et al., 2003) (Fig. 1). The propeptide domain contains conserved PRCGVPDV motive that binds to the zinc ion of the catalytic center via the cysteine residue in order to maintain the latency of the proenzyme (Van Wart and Birkedal-Hansen, 1990; Becker et al., 1995). The enzyme activation occurs by the propeptide cleavage that is responsible for disruption of cysteine-zinc ion interaction. The catalytic domain of MMP-9 contains, zinc-binding motif HExGHxxGxxH (where x states for any amino acids) highly conserved in all MMPs and responsible for overlapping its substrate specificity with other MMPs. A hemopexin-like domain at the carboxyl terminus of MMP9 is reported to be required for the binding of tissue inhibitor of
MMP-9 is an important enzyme involved in matrix remodeling during the normal processes of embryogenesis, tissue remodeling and development. In addition to its role in maintaining tissue homeostasis MMP-9 was shown to be activated in such pathologies as cancer (it modulates tumor micro-environment and enhances metastasis) or in acute and chronic neurological conditions e.g. stroke or multiple sclerosis (Kessenbrock et al., 2010; Yong et al., 2005). Recently, MMP-9 has also emerged as a novel regulator of physiological processes in healthy adult CNS, such as synaptic plasticity, learning and memory (Rivera et al., 2010) (Fig. 2). Matrix metalloproteinase-9 is expressed in such adult brain structures as hippocampus, cerebral cortex and cerebellum. It is mostly produced by neurons, but to some extent also by glia. In neurons, MMP-9 expression is induced by neuronal activity under physiological as well as pathological conditions such as epilepsy or stroke. Aberrant, and usually excessive MMP-9 gene expression has been linked to numerous disorders of the central nervous system (Dzwonek et al., 2004). The regulation of Mmp-9 gene promoter has been extensively studied in non-neuronal cells. In neurons, the most prominent transcription factors implicated in Mmp-9 gene activation are AP-1 and
∗ Corresponding author. Tel.: +48 22 589 2360. E-mail address: [email protected] (J. Wlodarczyk). 1357-2725/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2012.01.023
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M. Dziembowska, J. Wlodarczyk / The International Journal of Biochemistry & Cell Biology 44 (2012) 709–713
and then it is activated by proteolytic cleavage. It was demonstrated that neuronal stimulation releases the required inactive proMMP9, which is activated extracellularly. A number of proteases seem to be involved in cleaving off the propeptide, including MMPs themselves and, in particular, components of the plasminogen–plasmin system (Bruno and Cuello, 2006). Plasminogen conversion to plasmin activated by either tissue plasminogen activator or urokinase plasminogen activator plays a role in activation of proteolytic system composed of MMP-9 and its endogenous inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinases) (Dzwonek et al., 2004). MMP-9 is directly regulated by TIMP-1 but also by glycosylation and internalization (Yong, 2005). It should be emphasized that the MMPs are active very locally, at the sites of release, as well as very transiently, being rapidly inhibited by, probably co-released, TIMPs. Michaluk et al. (2007) have shown increased MMP-9 activity within 5 min after synaptic stimulation. Sbai et al. (2008) have shown that MMPs and TIMP-1 are secreted in 160–200 nm vesicles in a Golgi-dependent pathway. These vesicles distribute along microtubules and microfilaments, colocalise differentially with the molecular motors kinesin and myosin Va and undergo both anterograde and retrograde trafficking. MMP-9 vesicles are preferentially distributed in the somato-dendritic compartment and are found in dendritic spines (Sbai et al., 2008). It was also shown that in human fibrosarcoma cell line HT-1080 that MMP-9 release can occur via a SNARE (soluble NSF attachment protein receptor) dependent mechanism (Kean et al., 2009). In neurons such mechanism of MMP-9 secretion have not been described. Once secreted and activated MMP-9 causes the proteolytic degradation of its extracellular substrates e.g. proteins such as beta-dystroglycan, N-cadherin, membrane-bound receptors e.g. 1 containing integrins but also neurotrophins, such as brain derived neurotrofic factor (BDNF) or nerve growth factor (NGF). Probably, there are more physiological targets of the MMP-9 that need to be identified to fully understand its function at the synapse. It has been shown that activity-dependent substrate cleavage by synaptic metalloproteases and ␥-secretase decreases levels of synaptic proteins and diminishes synaptic transmission (Restituito et al., 2011). Fig. 1. Domain structure (left) and ternary structure (right) of MMP-9, composed of: a signal peptide (white), a propeptide (green), a catalytic domain (red) that contains a zinc ion (grey), a three tandem repeats of fibronectin type II inserts (blue) within the catalytic domain, a proline-rich and heavily O-glycosylated linker (dashed line), and a hemopexin-like domain (grey).
NF-B. In the promoter region of Mmp-9 gene, spanning about 1000 bp, three functional AP-1 and one NF-B binding site have been identified. The transcriptional regulator Yin Yang 1 (YY1) was shown to act as a strong repressor of Mmp-9 transcription in the rat hippocampus in vivo, as well as in the cultured neurons. Synaptic stimulation leads to YY1 dissociation from MMP-9 proximal promoter and activation of the gene expression (Rylski et al., 2008). Recently we have discovered an additional level of MMP-9 regulation in neurons, e.g. its local translation in synapto-dendritic compartment (Dziembowska et al., submitted for publication). MMP-9 mRNA is transported to the dendrites and locally translated upon synaptic stimulation in hippocampal neurons, and by LTP induced in the hippocampal dentate gyrus by high-frequency stimulation (HFS) of the medial perforant path in the rat brain. This data are consistent with previous studies showing MMP-9 mRNA and the protein to be present at the postsynaptic domains of glutamatergic synapses, e.g. at the dendritic spines (Konopacki et al., 2007; Gawlak et al., 2009; Wilczynski et al., 2008). Moreover, the enzymatic activity of MMP-9 was demonstrated at the synapses (Gawlak et al., 2009). MMP-9 is produced at the synapse and released into the extracellular space in an activity-dependent manner in a precursor form,
4. Role in synaptic plasticity The synaptic plasticity may be defined as a re-organization of the synaptic connections that comprises both, alterations at the morphological level and changes at the functional level. Enhanced neuronal activity and some aspects of plasticity are mimicked by experimental paradigms such as long-term potentiation (LTP). Recent studies indicate that spine structure can be regulated by extracellular matrix (ECM). Notably, an involvement of MMP9 in modulation of morphology of the dendritic spines has been reported. Release of MMP-9 and its local activity, in response to stimuli that produce enhancement of neuronal responses have been shown to affect spine morphology (Wang et al., 2008; Bilousova et al., 2009). Wang et al. (2008) reported that in acute hippocampal slices MMP-9 was necessary for enlargement of spines associated with long-term potentiation (LTP) induction. MMP-9 influence on dendritic spine enlargement and LTP coordinately implicates its instructive role in establishing persistent modifications in both synapse structure and function (Wang et al., 2008). Furthermore, Tian et al. (2007) have found that MMP-9, via cleavage of the intercellular adhesion molecule-5 (ICAM-5), can also cause elongation of dendritic filopodia in dissociated neuronal cultures. We have recently reported (Michaluk et al., 2011) using three independent experimental models (transgenic rat overexpressing autoactivating MMP-9, dissociated hippocampal cultures, and organotypic cultures) that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal
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Fig. 2. MMP-9 is locally released at the dendritic spines in a non-active form. The propeptide which block the enzymatic active site is cleaved off by a cascade of extracellular proteases, involving e.g. tPA-plasmin-plasminogen system. Once activated, MMP-9 cleaves ECM/CAMs, such as dystroglycan. The cleavage products act on integrin receptors to transduce the signals provoking actin cytoskeleton modifications underlying the growth of spines.
neurons. This dendritic effect was shown to be mediated by integrin 1 signaling and accompanied by changes in the decay time of miniature synaptic currents. Notably, MMP-9 increases lateral dendritic mobility of NMDAR and this effect as well as MMP-9 ability to affect spine morphology are abolished by the integrin 1 blocking antibody. Similarly, an incubation of dissociated neuronal culture with recombinant MMP-9 caused transformation of dendritic spines from mushroom- to filopodia-like protrusions (Bilousova et al., 2009). Notably, Bilousova et al. (2009) showed that in the fragile X mouse model (Fmr1 KO mice) an increase in proportion of filopodia to mature spines could be reversed by minocycline, whose pleiotropic effects include the ability to inhibit MMP-9. MMP-9 dependent changes in dendritic spine morphology appear to involve -dystroglycan, ICAM-5 and integrins, especially integrin 1 molecules (Nagy et al., 2006; Michaluk et al., 2007; Tian et al., 2007; Michaluk et al., 2009; Conant et al., 2010). The above findings apparently indicate on divergent effect of MMP-9 on spine morphology and raise the question regarding the factors playing the role in seemingly contradictory effects. Differences in MMP-9 dose (local vs. bath application), time-frames of enhanced MMP-9 activity associated with subsequent inhibitory effect by endogenous MMP-9 inhibitor, and the maturity of neurons used in the studied system appear to be involved. While the Wang et al. (2008) reported that MMP-9 promoted the maturation of dendritic spines, the others have instead shown that MMP-9 (Michaluk et al., 2011) or MMP-9 released products (Tian et al., 2007) can stimulate spine elongation. However, the authors have used a different brain slice models i.e. acute slices from P14 to P21 rats (Wang et al., 2008) vs. organotypic culture from P7 rats kept 11 DIV implemented by Michaluk et al. (2011). Furthermore, Wang et al. (2008) applied MMP-9 locally via a stimulating electrode, instead Michaluk et al. (2011) used bath application. The
local application might resemble physiological conditions more closely, since MMPs are thought to act both locally and transiently, as their activity is very strictly controlled. In contrast, the bath application resembles much more of a pathological situation when MMP-9 activity is out of control and would explain the mechanism of spine morphological changes during either stroke or epilepsy (Wilczynski et al., 2008). Similarly, Tian et al. (2007) used a fairly high dose of soluble ICAM-5 (for 72 h on 9 DIV neurons) and found that this treatment promote elongation of spines in a manner that was dependent on the presence of cell surface ICAM-5 mainly located on immature spines. This suggests that more mature neurons, which may express less surface ICAM-5 in comparison to immature spines, might respond differently. Additionally, the data on the effect MMP-9 inhibition on spine morphology (Bilousova et al., 2009; Tian et al., 2007; as well as our unpublished data) appear to suggest that the inhibition of MMP-9 may conclude the process of spine elongation and promotes the transformation of dendritic spines toward mature, mushroom shaped spines. Several recent reports have also demonstrated an importance of MMP-9 and its pivotal functional role in physiological long term potentiation (LTP) (see Wlodarczyk et al., 2011 for review) at diverse brain regions. Nagy et al. (2006) have provided evidence that both MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late phase of LTP (L-LTP). Moreover, the same authors demonstrated the impairment of CA3-CA1 L-LTP in slices, using MMP-9 knock-out mice as well as broad spectrum chemical inhibitors directed against MMPs. Simultaneously, Meighan et al. (2006) have shown that the inhibition of MMP-9 expression by the use of MMP-9 antisense oligonucleotides and activity (by the use of chemical inhibitors) altered the maintenance but not the induction of L-LTP. Functional role of MMP-9 in CA1 L-LTP has been also shown in vivo, by means of application
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of chemical inhibitors and neutralizing antibodies (Bozdagi et al., 2007). Similarly, Okulski et al. (2007) reported that blocking MMP-9 either by specific chemical inhibitor or by overexpression of TIMP1 impaired L-LTP (but not the induction of LTP) in the subiculum to prefrontal cortex pathway in freely moving rats as well as in the cortical slices. A role for MMPs, by means of application of a broad spectrum inhibitor, has also been revealed for the mossy fiber LTP in the hippocampus (Wojtowicz and Mozrzymas, 2010). In addition to the role of MMP-9 in physiological plasticity, various pathological conditions subserved by abnormal synaptic plasticity have been implied to involve MMP-9, e.g. epileptogenesis. The first data indicating the role of MMP/TIMP system in aberrant synaptic plasticity were provided by Nedivi et al. (1993) who have shown TIMP-1 mRNA up-regulation within the dentate gyrus (DG) after KA induced seizures. Szklarczyk et al. (2002) demonstrated that not only TIMP-1 gene expression but also MMP-9 expression (both at the level of mRNA, protein and enzymatic activity) was upregulated in DG following KA seizure. Furthermore, Wilczynski et al. (2008) demonstrated that MMP-9 is localized to excitatory synapses, where upon epileptic seizure both the MMP-9 protein level and enzymatic activity become strongly elevated. The same authors using two animal models of epileptogenesis, i.e. KA-evoked epilepsy and PTZ kindling demonstrated that the sensitivity to PTZ kindling was elevated in transgenic rats overexpressing MMP-9 and decreased in MMP-9 knockout mice. These finding were supported by several lines of evidence indicating increased synaptic accumulation of MMP-9 mRNA and neuronal MMP-9 levels following seizures (Konopacki et al., 2007; Michaluk et al., 2007; Gawlak et al., 2009; Rylski et al., 2008). A functional role of MMP-9 in the development of epilepsy has been supported by more recent studies (see Lukasiuk et al., 2011 for review and citations therein). MMP-9 plays also a functional role in various forms of synaptic plasticity characterized by drug addiction (see Rivera et al., 2010 for review). Brown et al. (2007), using intracerebral ventricular injection of a broad-spectrum MMP inhibitor prior to cocaine training, have shown that MMPs play a critical role in acquisition and reconsolidation of cocaine-induced place preference. Moreover the same authors (Brown et al., 2007) have shown that rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement. Furthermore, in MMP-9 KO mice diminished behavioral response to methamphetamine (MA) addictive treatment was reported (Mizoguchi et al., 2007). Additionally, mutant mice exhibited resistance to the inhibitory effect of treatment on dopamine transport activity (Mizoguchi et al., 2007). In vivo administration of acute dose of MA causes an increase in MMP-9 protein that occurs within 6 h in murine hippocampus and striatum. This is associated with MMP dependent cleavage of ICAM-5. The shedding ICAM-5 ectodomain that interacts with (1) integrin leads to increase in the phosphorylation of cofilin, an event permissive for spine expansion (Conant et al., 2011). It has also been reported that ethanol-induced impairment of watermaze learning correlated with reduced hippocampal and prefrontal cortex MMP-9 activity (Wright et al., 2003). More recently, it has been shown that MMP-9 in the spinal cord also contributes to development of physical dependence on morphine in mice (Liu et al., 2010).
5. Conclusions Matrix metaloproteinase-9 undergoes very complex regulation; it is secreted and activated in the extracellular space in response to enhanced neuronal activity. This enzyme can cleave and release signaling molecules from CAMs, which may affect morphology of existing dendritic spines. This effect is most probably mediated by integrin dependent signaling. Pivotal role of MMP-9 in the synaptic
plasticity at the level of gene expression, changes in dendritic spine morphology and synaptic transmission has been documented. Sustained increase in neuronal MMP-9 level has shown to contribute to the aberrant plasticity underlying neuronal pathologies such as epileptogenesis. In conclusion, the extracellular matrix (ECM) has been recently recognized as a critical factor affecting synapses, as it is forming integral synaptic component in addition to pre- and post-synapse, as well as glial invaginations. Although the role of ECM molecules such as MMP-9 in synaptic plasticity has recently started to be acknowledged, the questions regarding the exact nature of molecular events taking part in those phenomena, remains open. The ability of MMP-9, the ECM modifier, to release signaling molecules from the ECM has drawn recently considerable attention and stimulate further interest to better understanding of subcellular localization of active MMP-9, role of non-active proteinase as well as signaling transduction pathways. These data, together with the beneficial effects of MMP-9 on synaptic plasticity argue in a favor of multifaceted view on the role of the MMP-9 on synaptic plasticity and may eventually open a novel approaches for the development of new tools and adequate treatments for neurodegenerative disorders and drug addiction. Acknowledgments J.W. was supported by ERA-NET NEURON MODDIFSYN. M.D. was supported by grant from Polish Ministry of Science and Higher Education no. N N301 033134. This work was supported by the COST Action BM1001 “Brain Extracellular Matrix in Health and Disease”. We thank Prof L. Kaczmarek and Prof G.M. Wilczynski for valuable discussions and suggestions regarding the manuscripts. References Becker JW, Marcy AI, Rokosz LL, Axel MG, Burbaum JJ, Fitzgerald PM, et al. Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci 1995;4:1966–76. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 2009;46:94–102. Bozdagi O, Nagy V, Kwei KT, Huntley GW. In vivo roles for matrix metalloproteinase9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol 2007;98:334–44. Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci U S A 2006;103:6735–40. Brown TE, Forquer MR, Cocking DL, Jansen HT, Harding JW, Sorg BA. Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference. Learn Mem 2007;14:214–23. Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, Lim ST. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 2010;166:508–21. Conant K, Lonskaya I, Szklarczyk A, Krall C, Steiner J, Maguire-Zeiss K, et al. Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5. J Neurochem 2011;118:521–32. Dziembowska M, Milek J, Janusz A, Rejmak E, Romanowska E, Tiron A, Bramham C, Kaczmarek L. MMP-9 is locally translated in neurons. submitted for publication. Dzwonek J, Rylski M, Kaczmarek L. Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in neuronal physiology of the adult brain. FEBS Lett 2004;567:129–35. Gawlak M, Gorkiewicz T, Gorlewicz A, Konopacki FA, Kaczmarek L, Wilczynski GM. High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses. Neuroscience 2009;158:167–76. Kean MJ, Williams KC, Skalski M, Myers D, Burtnik A, Foster D, et al. VAMP3, syntaxin-13 and SNAP23 are involved in secretion of matrix metalloproteinases, degradation of the extracellular matrix and cell invasion. J Cell Sci 2009;122:4089–98. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141:52–67. Konopacki FA, Rylski M, Wilczek E, Amborska R, Detka D, Kaczmarek L, et al. Synaptic localization of seizure-induced matrix metalloproteinase-9 mRNA. Neuroscience 2007;150:31–9. Liu WT, Han Y, Liu YP, Song AA, Barnes B, Song XJ. Spinal matrix metalloproteinase9 contributes to physical dependence on morphine in mice. J Neurosci 2010;30:7613–23.
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