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 ␤1-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.actin ͉ cofilin ͉ integrin ͉ synaptic plasticity ͉ protein synthesis L ong-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 (4-6). 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 u...

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

“…There is no endogenous presence of ChABC in the brain, but there are naturally occurring proteolitic enzymes that include CSPGs in the list of their putative targets. One of these enzymes, MMP-9, was found to drive dendritic spine enlargement and LTP coordinately in hippocampal slices by activating the b-integrin pathway, leading to integrin-dependent cofilin inactivation and actin polymerization 36 . Our data suggest that the increased spine plasticity caused by the degradation of CSPGs leads to an increased susceptibility to activity-dependent potentiation of excitatory connectivity.…”

Integrin Dynamics Produce a Delayed Stage of Long-Term Potentiation and Memory Consolidation

“…Next, we tested whether the effects of TBS on FAK activation are dependent upon ␤1 integrins by infusing neutralizing antisera to the ␤1 integrin subunit at concentrations shown in previous studies to block both signaling initiated by integrin ligands in synaptoneurosomes (Bernard-Trifilo et al, 2005), and the contribution of ␤1 integrins to LTP (Bernard-Trifilo et al, 2005;Kramár et al, 2006;Wang et al, 2008); anti-mouse IgG (IgG) was infused in control preparations. As in prior work (Kramár et al, 2006), ␤1-neutralizing antisera did not influence baseline responses (fEPSP slope: ϩIgG ϭ 98 Ϯ 2%, ϩanti-␤1 ϭ 98 Ϯ 5%, percentage of ACSFcontrol values) or short-term potentiation immediately after TBS (fEPSP slope 1 min post-TBS: ϩIgG ϭ 252 Ϯ 36%, ϩanti-␤1 ϭ 264 Ϯ 20%; Fig.…”

Protein synthesis and consolidation of memory-related synaptic changes

“…Results from our laboratories and elsewhere (Fukazawa et al, 2003;Kramar et al, 2006;Krucker et al, 2000;B. Lin et al, 2005;Okamoto et al, 2009;Wang et al, 2008) led to the conclusion that the enlargement and stabilization of the spine actin cytoskeleton initiated by Theta Burst Simulation (TBS) may be a critical consolidating event. Specifically, potentiation induced with either TBS or high frequency stimulation elicits, and depends upon, new actin polymerization in dendritic spines (Fig.…”

“…Further analyses demonstrated that these structural events are driven by separate signaling streams that control the assembly (polymerization) and subsequent stabilization of the new actin filaments Fedulov et al, 2007;Kramar et al, 2006;Mantzur et al, 2009;Rehberg et al, 2010;Rex et al, 2009Rex et al, , 2010. Integrins, a group of transmembrane adhesion receptors that regulate the cytoskeleton at most types of cellular junctions (Brakebusch and Fassler, 2003), play a central role in these processes, as indicated by results of studies using toxins, small peptides, neutralizing antibodies, or genomic manipulations (Kramar et al, 2006;Nagy et al, 2006;Wang et al, 2008). Downstream intracellular signaling cascades (small GTPases and their effectors) initiated by integrins have also been linked to LTP stabilization (Rex et al, 2009).…”