New EMBO Member's Review: Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections?

Abstract

Matrix metalloproteinases (MMPs), together with their endogenous inhibitors (TIMPs) form an enzymatic system that plays an important role in a variety of physiological and pathological conditions. These proteins are also expressed in the brain, especially under pathological conditions, in which glia as well as invading in¯ammatory cells provide the major source of the MMP activity. Surprisingly little is known about the MMP function(s) in adult neuronal physiology. This review describes available data on this topic, which is presented in a context of knowledge about the MMP/TIMP system in other organs as well as in brain disorders. An analysis of the MMP and TIMP expression patterns in the brain, along with a consideration of their regulatory mechanisms and substrates, leads to the proposal of possible roles of the MMP system in the brain. This analysis suggests that MMPs may play an important role in the neuronal physiology, especially in neuronal plasticity, including their direct participation in the remodeling of synaptic connectionsÐa mechanism pivotal for learning and memory.

Enzymatic processing of β‐dystroglycan recombinant ectodomain by MMP‐9: Identification of the main cleavage site

“…However, its fairly low enzymatic efficiency under our conditions might indicate that this event is finely modulated by conformational changes of b-DG. The recent discovery of a b-DG processing carried out by MMP-9 in response to enhanced neuronal activity (23,24) would strengthen the hypothesis that MMP-9 cooperates with the DG complex in the signal transduction.…”

“…Interestingly, b-DG has been proposed to be the first substrate digested by MMP-9 in response to enhanced neuronal activity, playing a role in synaptic plasticity, learning and memory (23,24). These data suggest that modulating the a-DG/b-DG interaction may have a precise functional role and that MMP-9 may be involved in this physiological process.…”

Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation

“…MMPs (matrix metalloproteinases) and ADAMs (a disintegrin and metalloproteinase) have the ability to cleave all major ECM protein components under physiological conditions (4,5). A concerted action of different proteases may, therefore, be highly relevant to the construction and physiology of neural circuits (6,7). Numerous studies have implicated ADAMs in the formation of neural connections in the developing nervous system (8)(9)(10)(11).…”

Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain

“…A very promising MMP physiological brain target molecule is b-dystroglycan [65,66]. Dystroglycan is a cell surface protein protruding from postsynaptic membrane and bound (probably throughout the synaptic cleft) to presynaptic neurexins, implicated in neurotransmitter release [64,67].…”

“…Genetic evidence implicated dystroglycan in long term potentiation (LTP), a model of neuronal plasticity [68]. These results and considerations have prompted us to propose that MMP-9 can be involved in synaptic plasticity by modifying the local environment and even serve as a retrograde messenger at activated synapses [66].…”