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Proc Natl Acad Sci U S A. Dec 9, 2008; 105(49): 19520–19525.
Published online Dec 1, 2008. doi:  10.1073/pnas.0807248105
PMCID: PMC2614793
Neuroscience

Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately

Abstract

Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through β1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.

Keywords: actin, cofilin, integrin, synaptic plasticity, protein synthesis

Long-lasting memory is based on long-term modifications of synapse structure and function. In hippocampal area CA1, naturalistic patterns of theta-stimulation readily induce long-term potentiation (LTP) of the excitatory, glutamatergic Schaffer collateral afferent inputs that target dendritic spines (1), which are small, actin-rich dendritic protrusions that harbor the majority of the excitatory synapses (2). Studies show that dendritic spines undergo significant morphological remodeling in association with long-lasting plasticity (3). Spine growth, for example, is associated with the induction of LTP and is thought to be important for supporting persistent changes in synaptic strength (46). However, little is known about signals that instruct and coordinate persistent modifications in synapse structure and function during LTP.

Dendritic spine morphology and synaptic potentiation can both be dynamically modulated by proteins of the extracellular matrix (ECM) and the cell-surface proteins with which they interact, which has long fueled the idea that regulated ECM remodeling has an important role in synaptic plasticity (7). How precisely such remodeling could occur is not understood. In other tissues, regulated proteolytic remodeling of the ECM by matrix metalloproteinases (MMPs) is important for driving changes in cell shape and movement (8). MMPs are mostly secreted, extracellularly-acting proteases that function under various contexts in local pericellular remodeling, which has both beneficial and maladaptive consequences. In brain, they are secreted by neurons and glia in an inactive (pro) form, and they become proteolytically active when several regulatory steps that result in removal of the propeptide are triggered in response to specific stimuli (9). For example, studies have shown that in response to LTP induction, MMP-9 rapidly becomes proteolytically active at perisynaptic sites and essential for maintenance of LTP (1013). Thus, perisynaptic MMP-9 proteolysis in response to LTP induction may be critical for local remodeling of dendritic spine structure and function necessary to support long-term synaptic plasticity.

Here, we test this idea by combining 2-photon time-lapse imaging with whole-cell patch clamp recording from area CA1 neurons to investigate directly the role of MMP-9 in LTP-associated structural and functional plasticity. The results identify an instructive role for MMP-9 in coordinating synaptic structural and functional plasticity during LTP.

Results

Stable Spine Expansion and LTP Both Require MMP Proteolysis.

We blocked endogenous MMP proteolysis with bath-applied MMP inhibitors while applying a theta-burst pairing (TBP) protocol that induces rapid and persistent spine enlargement and LTP (5). Spine size and synaptic responses [excitatory postsynaptic potentials (EPSPs)] were monitored simultaneously in CA1 neurons by 2-photon time-lapse imaging and whole-cell patch clamp recording (Fig. 1A). Spines were visualized by intracellular labeling with an inert fluorescent dye, calcein, contained in the recording patch pipette. A stimulating glass electrode was positioned ≈20 μm from the imaged spines to elicit EPSPs and TBP, a configuration that maximizes the likelihood that synapses on the imaged spines are activated (5, 14, 15). In the absence of MMP inhibitors, TBP induced a rapid and persistent increase in spine volume (Fig. 1B) and an immediate but small increase in EPSP slope, which gradually increased further until reaching a plateau by ≈30 min (Fig. 1C) as expected (5). In contrast, in the presence of an MMP-9 inhibitor (Inhibitor II), TBP produced a spine enlargement and synaptic potentiation that were transient (Fig. 1 A–C). Spine volume increased immediately to values comparable with those in untreated slices, but then returned gradually to baseline values (Fig. 1B). In parallel, EPSP slope also increased immediately to levels comparable with those seen in untreated slices, but then fell to baseline levels (Fig. 1C). We obtained identical results by using a different MMP inhibitor, GM6001 [supporting information (SI) Fig. S1]. Control experiments verified that the MMP inhibitors had no effects on either basal synaptic transmission, as expected (10, 11), or spine volume (Fig. S2). These data demonstrate that blocking endogenous MMP activity during LTP induction impairs stable spine expansion and prevents the full expression of synaptic potentiation.

Fig. 1.
Persistence of TBP-triggered spine expansion and LTP requires MMP proteolysis. (Ai). A representative CA1 neuron showing the position of the local stimulating (Stim) and whole-cell recording (Rec) electrodes. (Scale bar: 50 μm.) (Aii and Aiii ...

Locally Delivered MMP-9 Causes Spine Expansion and Synaptic Potentiation.

The experiments above indicate that MMP activity is necessary for persistence of TBP-induced spine enlargement, but is it sufficient for inducing persistent spine enlargement alone in the absence of TBP? We answered this by using the combined imaging/recording configuration described above while briefly puffing MMP-9 through the stimulating microelectrode onto naive (unpotentiated) spines. We found that local exposure of naive spines to MMP-9 (0.5 μg/mL; 30 min) produced a persistent expansion in the volume of the dendritic spine heads in a majority of the spines imaged (Fig. 2A, arrowheads) and contemporaneously produced a consistent increase in EPSP slope that reached a plateau in 30–40 min and persisted stably throughout the recording period (Fig. 2 A and B). When all of the spines within the imaged regions near the stimulating pipette were examined as a group, the average spine volume increased significantly compared with baseline levels (Fig. 2C and Fig. S3A). In contrast, the inactive pro-MMP-9 did not affect either EPSPs or spine volume (Fig. 2 B and C and Fig. S3B), presumably because the endogenous mechanisms leading to removal of the prosequence, normally triggered by TBS, are not engaged in the absence of TBS. Further analyses showed substantial spine expansion in response to MMP-9 over the entire range of initial spine volumes (Fig. S3C), indicating that both small and large spines are capable of expansion in response to MMP-9, consistent with several recent studies (5, 16). Together, these results demonstrate that local MMP-9 proteolysis is both necessary and sufficient for persistent spine enlargement and potentiation.

Fig. 2.
MMP-9 drives persistent spine expansion and LTP at naive spines. (A) A representative experiment from a single CA1 neuron showing persistent spine expansion and synaptic potentiation after brief puffing of MMP-9 onto naive spines. Numbers indicate corresponding ...

TBP Occludes MMP-9-Induced Structural and Functional Plasticity.

We next asked whether the MMP-9-induced plasticity is the same spine and synaptic modifications that are triggered by TBP. We addressed this by occlusion experiments, in which TBP was applied first followed 15 min later by local delivery of MMP-9 to the TBP-potentiated spines through the stimulation pipette. TBP produced an immediate spine expansion and potentiation as expected, but subsequent delivery of MMP-9 did not produce further spine expansion or potentiation (Fig. S4). These results suggest that TBP and MMP-9 engage common signaling pathways or expression mechanisms.

Integrin Receptors Mediate MMP-9-Induced Spine Expansion and Synaptic Potentiation.

We next investigated the signaling cascade leading from MMP-9 activity to spine enlargement. We focused on integrins because they can regulate cell shape on binding MMP-exposed matrix proteins (8). We preincubated slices with a function-neutralizing β1-integrin antibody before exposure to MMP-9, because the majority of hippocampal integrin heterodimers contain a β1 subunit (17, 18), and such heterodimers are required for consolidation of theta-LTP (19, 20). In the presence of the blocking antibody, MMP-9-induced spine expansion (Fig. 3A) and synaptic potentiation (Fig. 3B) were both abrogated. Control experiments confirmed that the neutralizing antibody alone had no effects on baseline spine morphology or synaptic physiology (Fig. S5) (10). Integrins drive changes in cell shape by affecting the actin cytoskeleton (21). Accordingly, we found that internal perfusion of the actin polymerizing inhibitor latrunculin A (latA, 0.1 μM) delivered through the patch pipette eliminated MMP-9-induced spine expansion and synaptic potentiation (Fig. S6).

Fig. 3.
MMP-9-induced structural and functional plasticity is mediated by integrins. (A) Preincubation with a neutralizing β1-integrin antibody prevents MMP-9-induced spine expansion. (B) Preincubation with β1-integrin antibody also prevents MMP-9-induced ...

MMP-9 Triggers Integrin-Dependent Cofilin Phosphorylation in Spines.

The results above suggest an important requirement for actin remodeling in persistent spine enlargement and synaptic potentiation. What regulates MMP-9-driven actin remodeling? Actin depolymerizing factor (ADF)/cofilin, among others, has F-actin severing and depolymerizing activity (22) and is negatively regulated by phosphorylation at a single site (23). Previous studies show that LTP causes increased dendritic spine content of phosphorylated cofilin (24), whereas inhibiting cofilin phosphorylation impairs LTP maintenance (25). We tested whether MMP-9-induced spine enlargement was associated with increased levels of phosphorylated cofilin. Slices were bath-exposed briefly to MMP-9, which produces persistent potentiation of CA3–CA1 synapses by 30 min posttreatment (10). Lysates were then probed with antisera specific to cofilin phosphorylated at Ser-3 and examined by Western blotting. MMP-9 induced a significant increase in levels of phosphorylated cofilin, without effects on total cofilin protein levels (Fig. 4A). This increase was blocked by the β1-integrin-neutralizing antibody, confirming that MMP-9-mediated effects on actin remodeling are mediated through integrins. We verified the increased levels of phosphocofilin in MMP-9-potentiated slices anatomically by using immunocytochemistry (Fig. 4 B and C). We found significantly greater numbers of phosphocofilin-labeled puncta within CA1 stratum radiatum, the site of the potentiated synapses, in comparison with control slices; such labeled puncta were significantly larger in comparison with those from control slices, which could not be attributed to differences in fluorescence intensity (data not shown). Coimmunolabeling with the excitatory postsynaptic density marker PSD-95 confirmed that the majority of such phosphocofilin-labeled puncta were associated with dendritic spines (Fig. 4C), as expected (see further discussion in SI Text, Note 1) (24, 26).

Fig. 4.
MMP-9 drives integrin-dependent cofilin phosphorylation in dendritic spines. (A) Representative Western blotting showing levels of phosphocofilin (p-cof) and total cofilin (cof) in untreated control sections, ones treated with MMP-9, ones treated with ...

Postsynaptic Exocytosis or Protein Synthesis Is Required for MMP-9 Potentiation but Not Initial Spine Enlargement.

We next asked whether the MMP-9-induced spine enlargement was mechanistically dissociable from MMP-9-induced potentiation. We investigated this first by inhibiting postsynaptic exocytosis with internal loading of the light chain of botulinum toxin type B (BoTox, 0.5 μM) while exposing imaged spines to MMP-9 (Fig. 5 A–C). Postsynaptic exocytosis is required for LTP (27), and studies suggest that LTP-associated spine expansion is unstable (5) or absent (28) when exocytosis is blocked. Under conditions where exocytosis in the postsynaptic neuron was blocked, MMP-9-induced potentiation was mostly eliminated (Fig. 5 A and B). In contrast, MMP-9-induced spine expansion occurred initially and appeared identical to that for control neurons exposed to MMP-9 alone (Fig. 5 A and C). However, such initial expansion was transient, and it decayed significantly from initial peak values (Fig. 5 A and C).

Fig. 5.
Blocking postsynaptic exocytosis or protein synthesis prevents MMP-9-induced potentiation and destabilizes MMP-9-induced spine expansion. (A) Sample images and EPSP traces showing the transient spine expansion (arrowheads) and small increase in EPSP size ...

We then tested the requirement for protein synthesis in MMP-9 structural and functional plasticity, because previous studies have indicated that in the presence of protein synthesis inhibitors, LTP is largely blocked and spine expansion becomes unstable (5, 29). We found that in the presence of cycloheximide, MMP-9 potentiation was greatly reduced and did not persist (Fig. 5D). In contrast, MMP-9-induced spine expansion occurred initially and reached values comparable with controls, but thereafter decayed steadily to baseline (Fig. 5E). Together, these results demonstrate that MMP-9-induced spine expansion occurs initially even when MMP-9 potentiation is absent or greatly diminished. This result suggests that the 2 forms of plasticity are expressed independently, but their persistence requires mechanistic interactions between them.

Discussion

Induction of LTP leads rapidly to perisynaptic MMP-9 proteolysis (10, 11). We show here that such MMP-9 proteolysis is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both forms of MMP-9-driven plasticity require β1-integrin-dependent actin remodeling and protein synthesis. When MMP activity is eliminated during TBP, both spine enlargement and potentiation are transient. Our results suggest that MMP-9 functions during LTP as a local, instructive extracellular signal that consolidates synaptic structural and functional modifications coordinately, ensuring persistent modifications critical for learning and memory (30, 31).

After TBP, there is an immediate increase in both spine size and EPSPs. The former is presumably attributable to rapid actin remodeling, at least partially mediated by cofilin inactivation, occurring seconds to minutes after LTP induction (4, 5, 20, 24, 3234), and the latter likely to rapid phosphorylation of AMPA receptors (AMPARs) (35). The MMP blockers had no effect on the immediate, TBP-triggered changes in spine size and potentiation, indicating that such rapid plasticity is mechanistically independent of MMP proteolysis. Proteolysis is probably maximally active later than the immediate forms of TBP-triggered plasticity, because increases in MMP-9 levels and proteolysis are detectable by 15–30 min after LTP induction (10, 11). NMDA receptors are required for such activation, but the downstream steps that then lead to MMP activation remain unknown and presumably account for some delay. It is conceivable that the onset of MMP-9 proteolysis could occur sooner, because pro-MMP-9 is present within the neuropil (10, 36) and could in theory be quickly activated by signaling molecules such as nitric oxide (37) or BDNF (38) that are released by LTP induction (39).

The immediate TBP-triggered increase in spine size and potentiation is followed by a consolidation process through which both structural and functional forms of plasticity are stabilized over the first ≈30 min (5, 40, 41). Studies suggest that although initial TBP-triggered spine expansion and LTP occur independently of each other, the 2 forms of plasticity then interact to enable consolidation of both (5, 6, 16). Our results are consistent with this observation and suggest that MMP-9 is an active component of the consolidation process, thereby having an instructive role in both spine expansion and synaptic potentiation. First, onset of LTP-triggered MMP-9 proteolysis matches closely the timeframe of consolidation; the fact that MMP inhibitors blocked persistence of TBP-triggered spine enlargement and potentiation is consistent with impairment in consolidation. Second, the effects of MMP inhibitors on stability of LTP are time-dependent, becoming ineffective after the period of consolidation (10). Third, MMP-9-driven spine enlargement and potentiation were both mediated exclusively by β1-integrins and require protein synthesis. It has been established that β1-integrins are critical for consolidation of theta-LTP and actin polymerization (18, 20, 42). Although it remains unknown precisely how MMP-9 engages integrin signaling, proteolysis of perisynaptic ECM could expose latent recognition sequences that then activate cell-surface integrins (43).

We found that MMP-9/integrin-dependent cytoskeletal reorganization, presumably mediated in part by MMP-9-triggered inactivation of cofilin, is a critical and common effector of both MMP-9-induced structural and functional plasticity. Potentiation associated with stable LTP involves insertion and synaptic incorporation of new AMPARs, a process that occurs on the order of 15–20 min post-LTP induction and is thought to require actin remodeling (5, 6, 28, 44, 45). The absence of MMP-9-induced potentiation in the presence of latA may reflect disruption of MMP-9/integrin-dependent trafficking of AMPARs. Although this possibility remains to be tested, β3-integrins regulate homeostatic synaptic plasticity through AMPA receptor trafficking (46). In addition to the expression of stable potentiation, synaptic incorporation of glutamate receptor 1 also appears necessary for LTP-associated initial spine expansion to persist (6, 16). Our finding that blocking postsynaptic exocytosis prevented MMP-9-induced potentiation, but affected only the stability of the MMP-9-induced spine expansion, suggests that MMP-9/integrin-dependent pathway controls AMPAR insertion, which confers subsequent stability on spine enlargement, and is consistent with previous studies showing that postsynaptic exocytosis is required for stable spine expansion and potentiation (5). Protein synthesis is also required for consolidating spine expansion and LTP (5, 29), and our data are consistent with this requirement for MMP-9-induced structural and functional plasticity. Our data do not distinguish whether such protein synthesis is downstream of integrin activation, or whether it is downstream of an additional, unidentified MMP-9-triggered pathway. In any event, MMP-9 is activated in hippocampus by inhibitory avoidance learning and is required for consolidating memory (47, 48). Thus, the cellular plasticity mechanisms we describe here likely underlie the contribution of MMP-9 to cognitive function.

Materials and Methods

Animals.

Acute hippocampal slices (350-μm thick) were from 14- to 21-day-old Sprague–Dawley rats. Use of the animals conformed to institutional and National Institutes of Health guidelines.

Whole-Cell Recordings, Image Acquisition, and Analysis.

Methods and reagents are described in SI Text, Note 2. MMP inhibitors, β1-integrin-blocking antibody, and cycloheximide were bath-applied; and active- or inactive- (pro)-MMP-9 was delivered locally through the glass stimulating pipette by controlled pressure pulses. Imaging was performed on a 2-photon laser scanning system. We verified that the various experimental conditions did not cause a substantial shift in the distribution of spine volume by calculating the percentage of imaged spines that show significant increases in volume (Fig. S7).

Western Blotting of MMP-9-Treated Sections.

Methods are detailed in SI Text, Note 3. Slices were bath-exposed to MMP-9 (30 min) in the presence or absence of β1-integrin-blocking antibody; control sections were untreated. After washout (30 min), whole-hippocampal lysates were prepared. Protein was separated by SDS/14% PAGE and probed with anti-phosphocofilin and anti-cofilin antibodies.

Immunolabeling and Analysis.

Methods are detailed in SI Text, Note 4. Slices were exposed to MMP-9 or left untreated as described above. After fixation, they were processed immunofluorescently for codistribution of phosphocofilin and PSD-95 and analyzed with Metamorph.

Statistical Analysis.

All data are expressed as mean ± SEM. Statistical analyses are listed in the text and individual figure legends.

Supplementary Material

Supporting Information:

Acknowledgments.

We thank Dr. Vanja Nagy for help and discussion at early stages of the project. G.W.H. was supported by National Institute of Mental Health Grant MH-075783. Q.Z. was supported by grants from the Whitehall Foundation and Ellison Medical Foundation.

Footnotes

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0807248105/DCSupplemental.

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