Effects of matrix metalloproteinase inhibition on short‐ and long‐term plasticity of schaffer collateral/CA1 synapses

Meighan, Peter C.; Meighan, Starla E.; Davis, Christopher J.; Wright, John W.; Harding, Joseph W.

doi:10.1111/j.1471-4159.2007.04682.x

Cited by 89 publications

(115 citation statements)

References 28 publications

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“…It is notable that recent measurements in the intact hippocampal mossy fiber-CA3 projection, showed that MMP inhibition did not alter PPF, but did reduce LTP in the first minutes following HFS (Wojtowicz and Mozrzymas, 2010). While the importance of MMP mediation in Schaffer collateral PPF is controversial (Meighan et al, 2007;Nagy et al, 2006), our results suggest that in the complex TBI + BEC insult, MMPs have less influence on PPF short-term plasticity. Collectively, our electrophysiological data are consistent with the hypothesis that postsynaptic activity may be more vulnerable to changes in ADAM-10/Ncadherin expression, preferentially contributing to greater deficits in synaptic efficacy under maladaptive conditions.…”

Section: Discussioncontrasting

confidence: 51%

“…It is also possible that collateral inhibition of the secreted MMPs 3 and 9 contributes to the attenuated LTP response reported here. While each of these MMPs has been shown to support LTP maintenance and synaptic stability (Conant et al, 2010;Meighan et al, 2007;Nagy et al, 2006;Wang et al, 2000), such effects were demonstrated by the application of MMP inhibitors at the time of LTP trials, conditions that do not directly address the timedependent processes of the present experimental paradigm. A more likely explanation of the effect of GM6001 on LTP would be that it attenuates ADAM-10 lytic shedding of N-cadherin, thereby increasing stabilization of the post-synaptic density (Isaac et al, 1995;Liao et al, 1995), and facilitating the trafficking of synaptic AMPA receptors (Bredt and Nicoll, 2003;Malenka and Nicoll, 1999;Nuriya and Huganir, 2006).…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

Warren

Reeves²,

Phillips³

2012

Journal of Neurotrauma

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Matrix metalloproteinases (MMPs) influence synaptic recovery following traumatic brain injury (TBI). Membrane type 5-matrix metalloproteinase (MT5-MMP) and a distintegrin and metalloproteinase-10 (ADAM-10) are membrane-bound MMPs that cleave N-cadherin, a protein critical to synapse stabilization. This study examined protein and mRNA expression of MT5-MMP, ADAM-10, and N-cadherin after TBI, contrasting adaptive and maladaptive synaptogenesis. The effect of MMP inhibition on MT5-MMP, ADAM-10, and N-cadherin was assessed during maladaptive plasticity and correlated with synaptic function. Rats were subjected to adaptive unilateral entorhinal cortical lesion (UEC) or maladaptive fluid percussion TBI + bilateral entorhinal cortical lesion (TBI + BEC). Hippocampal MT5-MMP and ADAM-10 protein was significantly elevated 2 and 7 days postinjury. At 15 days after UEC, each MMP returned to control level, while TBI + BEC ADAM-10 remained elevated. At 2 and 7 days, N-cadherin protein was below control. By the 15-day synapse stabilization phase, UEC Ncadherin rose above control, a shift not seen for TBI + BEC. At 7 days, increased TBI + BEC ADAM-10 transcript correlated with protein elevation. UEC ADAM-10 mRNA did not change, and no differences in MT5-MMP or Ncadherin mRNA were detected. Confocal imaging showed MT5-MMP, ADAM-10, and N-cadherin localization within reactive astrocytes. MMP inhibition attenuated ADAM-10 protein 15 days after TBI + BEC and increased N-cadherin. This inhibition partially restored long-term potentiation induction, but did not affect pairedpulse facilitation. Our results confirm time-and injury-dependent expression of MT5-MMP, ADAM-10, and N-cadherin during reactive synaptogenesis. Persistent ADAM-10 expression was correlated with attenuated N-cadherin level and reduced functional recovery. MMP inhibition shifted ADAM-10 and N-cadherin toward adaptive expression and improved synaptic function.

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 87%

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

Warren

Reeves²,

Phillips³

2012

Journal of Neurotrauma

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“…It has been shown that MMP-9 is rapidly and transiently activated in an NMDA receptor-and a protein synthesis-dependent manner during the late phase of long-term potentiation (LTP) (Nagy et al, 2006). MMP-9 is activated perisynaptically after LTP induction and is required for LTP maintenance (Bozdagi et al, 2007;Meighan et al, 2007;Okulski et al, 2007). Recent studies indicate also the important role of MMP-9 in shaping dendritic spine morphology (Wang et al, 2008;Bilousova et al, 2009;Michaluk et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Local Translation of Matrix Metalloproteinase-9

et al. 2012

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Local, synaptic synthesis of new proteins in response to neuronal stimulation plays a key role in the regulation of synaptic morphogenesis. Recent studies indicate that matrix metalloproteinase-9 (MMP-9), an endopeptidase that regulates the pericellular environment through cleavage of its protein components, plays a critical role in regulation of spine morphology and synaptic plasticity. Here, we sought to determine whether MMP-9 mRNA is transported to dendrites for local translation and protein release. First, dendritic transport of MMP-9 mRNA was seen in primary hippocampal neuronal cultures treated with glutamate and in dentate gyrus granule cells in adult anesthetized rats after induction of long-term potentiation. Second, rapid, activity-dependent polyadenylation of MMP-9 mRNA; association of the mRNA with actively translating polysomes; and de novo MMP-9 protein synthesis were obtained in synaptoneurosomes isolated from rat hippocampus. Third, glutamate stimulation of cultured hippocampal neurons evoked a rapid (in minutes) increase in MMP-9 activity, as measured by cleavage of its native substrate, ␤-dystroglycan. This activity was reduced by the polyadenylation inhibitor, thus linking MMP-9 translation with protein function. In aggregate, our findings show that MMP-9 mRNA is transported to dendrites and locally translated and that the protein is released in an activity-dependent manner. Acting in concert with other dendritically synthesized proteins, locally secreted MMP-9 may contribute to the structural and functional plasticity of the activated synapses.

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“…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 (10)(11)(12)(13). 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.…”

mentioning

confidence: 99%

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

Wang

Bozdagi

Nikitczuk

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

295

323

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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...

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Effects of matrix metalloproteinase inhibition on short‐ and long‐term plasticity of schaffer collateral/CA1 synapses

Cited by 89 publications

References 28 publications

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

Activity-Dependent Local Translation of Matrix Metalloproteinase-9

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

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