Molecules in focus
MMP9: A novel function in synaptic plasticity

https://doi.org/10.1016/j.biocel.2012.01.023Get rights and content

Abstract

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.

Highlights

► MMP-9 mRNA is locally translated in neurons and released in response to enhanced synaptic activity. ► MMP-9 is present at the dendritic spines bearing asymmetric synapses. ► MMP-9 influences dendritic spine morphology and plays a key role in synaptic plasticity associated with learning and memory.

Introduction

The matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes which operate extracellularly and are able to degrade components of the extracellular matrix ECM (Woessner, 1991).

Section snippets

Structure

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

Expression and activation in neurons

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

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 MMP-9 in modulation of morphology of the dendritic spines

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

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.

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