Synaptically Released Matrix Metalloproteinase Activity in Control of Structural Plasticity and the Cell Surface Distribution of GluA1-AMPA Receptors

Abstract

Synapses are particularly prone to dynamic alterations and thus play a major role in neuronal plasticity. Dynamic excitatory synapses are located at the membranous neuronal protrusions called dendritic spines. The ability to change synaptic connections involves both alterations at the morphological level and changes in postsynaptic receptor composition. We report that endogenous matrix metalloproteinase (MMP) activity promotes the structural and functional plasticity of local synapses by its effect on glutamate receptor mobility and content. We used live imaging of cultured hippocampal neurons and quantitative morphological analysis to show that chemical long-term potentiation (cLTP) induces the permanent enlargement of a subset of small dendritic spines in an MMP-dependent manner. We also used a superresolution microscopy approach and found that spine expansion induced by cLTP was accompanied by MMP-dependent immobilization and synaptic accumulation as well as the clustering of GluA1-containing AMPA receptors. Altogether, our results reveal novel molecular and cellular mechanisms of synaptic plasticity.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…MMPs are the family of zinc-dependent endopeptidases that degrade ECM proteins and are permissive to a number of events classically associated with synaptic plasticity, including morphologic changes in dendritic spines (Michaluk et al, 2011;Stawarski et al, 2014;Verslegers et al, 2015), NMDAR lateral diffusion, and AMPAR phosphorylation and insertion (Michaluk et al, 2009;Szepesi et al, 2014). Specifically, MMP-2 and MMP-9 play important roles in aberrant synaptic plasticity associated with neurologic disorders (Mizoguchi et al, 2011;Stawarski et al, 2014), with recent research demonstrating the importance of MMPs in drug behavioral effects and relapse.…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…[12][13][14] Notably, a well-recognized feature of Fragile X syndrome in humans (ie, elongated dendritic spines that are reproduced in FMRP knockout mice) is accompanied by the excessive production of MMP-9 that, when inhibited, normalizes the spines and alleviates other pathological symptoms, both behavioral and peripheral. 15,16 The well-documented and mechanistically explained role of MMP-9 in driving synaptic plasticity coincides with the function of MMP-9 in phenomena that rely on plasticity, such as learning and memory, addiction, and epileptogenesis, which have been studied in various animal models.…”

A novel phosphorylation site of N-methyl- d -aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia

“…For chemical LTP induction, we followed the protocol reported previously (Qiu et al, 2013;Szepesi et al, 2014). Briefly, the cultures were transferred from Neurobasal medium to extracellular solution (ECS) containing: 150 mM NaCl, 2 mM CaCl 2 , 5 mM KCl, 10 mM HEPES (pH 7.4), 30 mM glucose, 50 μM forskolin, 0.1 μM rolipram, and 50 μM picrotoxin for indicated time and then processed to western blot analysis.…”

“…We wondered whether S1284 was also participated in LTP and learning process. To answer the question, the well-established chemical LTP (cLTP) paradigm (Otmakhov et al, 2004;Qiu et al, 2013;Szepesi et al, 2014) was employed in this study. Chemical LTP was induced in hippocampal cultures by co-application of PKA activators (forskolin and rolipram) and free of Mg 2+ to increase spontaneous neuronal activation and activate NMDA receptors.…”