The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Abstract

Matrix metalloproteinases (MMPs) are a family of extracellularly acting proteolytic enzymes with well-recognized roles in plasticity and remodeling of synaptic circuits during brain development and following brain injury. However, it is now becoming increasingly apparent that MMPs also function in normal, nonpathological synaptic plasticity of the kind that may underlie learning and memory. Here, we extend this idea by investigating the role and regulation of MMP-9 in an inhibitory avoidance (IA) learning and memory task. We demonstrate that following IA training, protein levels and proteolytic activity of MMP-9 become elevated in hippocampus by 6 h, peak at 12-24 h, then decline to baseline values by ∼72 h. When MMP function is abrogated by intrahippocampal infusion of a potent gelatinase (MMP-2 and MMP-9) inhibitor 3.5 h following IA training, a time prior to the onset of training-induced elevation in levels, IA memory retention is significantly diminished when tested 1-3 d later. Animals impaired at 3 d exhibit robust IA memory when retrained, suggesting that such impairment is not likely attributed to toxic or other deleterious effects that permanently disrupt hippocampal function. In anesthetized adult rats, the effective distance over which synaptic plasticity is impaired by a single intrahippocampal infusion of the MMP inhibitor of the kind that blocks IA memory is ∼1200 µm. Taken together, these data suggest that IA training induces a slowly emerging, but subsequently protracted period of MMP-mediated proteolysis critical for enabling long-lasting synaptic modification that underlies long-term memory consolidation.New information is learned and remembered through functional and structural modifications of synaptic connections (Bliss and Collingridge 1993;Rogan et al. 1997;Rioult-Pedotti et al. 1998Jorntell and Hansel 2006;Pastalkova et al. 2006;Whitlock et al. 2006). Several kinds of learning and memory tasks have been shown to drive changes in neurotransmitter receptor function and/or localization (Cammarota et al. 1995;Bevilaqua et al. 2005;Rumpel et al. 2005;Whitlock et al. 2006), as well as induce over time changes in synapse number or morphology (O'Malley et al. 2000;Geinisman et al. 2001;Eyre et al. 2003;Leuner et al. 2003;Maviel et al. 2004;Lamprecht et al. 2006;Rekart et al. 2007). These observations suggest that there must be learninginduced cellular mechanisms for coordinating functional and structural remodeling of synaptic connectivity to enable longterm memory, but there is little known about the molecules that could fulfill such a role.Learning-related, regulated extracellular proteolysis could be one mechanism for coordinating functional and structural synaptic plasticity, thereby enabling memory (Huang et al. 1996;Madani et al. 1999;Calabresi et al. 2000;Pawlak et al. 2002;Tamura et al. 2006). It is well-recognized that extracellular matrix (ECM) proteins as well synaptic cell adhesion molecules contribute to both functional and structural aspects of synaptic plasticity, are modified by l...

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

“…For example, inhibition of MMP-3 and MMP-9 in the hippocampus was shown to disrupt spatial learning and memory in rats (Meighan et al, 2006;Wright et al, 2007). MMP-9 is activated by inhibitory avoidance learning and is required for long-term memory (Nagy et al, 2007). Further, MMP-9 is activated upon LTP induction and LTP maintenance, and MMP-9-induced synaptic potentiation is mediated, in part, through integrin-b1 receptors (Wang et al, 2008).…”

Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice

“…Moreover, others have demonstrated a role for MMP-9 in synaptic plasticity, showing the activity-dependent dendritic localization and translation of MMP-9 following the induction and maintenance of long-term potentiation and the elongation and thinning of dendritic spines induced by MMP-9 activity (Nagy et al, 2006; Bozdagi et al, 2007; Okulski et al, 2007; Wang et al, 2008; Michaluk et al, 2011; Dziembowska et al, 2012). MMP-9 levels are elevated in mild cognitive impairment (Bruno et al, 2009) and during experimental epileptogenesis (Wilczynski et al, 2008), but MMP-9 activation is also necessary for inhibitory avoidance learning and long-term memory (Nagy et al, 2007). New treatments that focus on more specific MMP-9 inhibitors may prove beneficial for the treatment of FXS and possibly other cognitive disorders.…”

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

“…Our data do not distinguish whether such protein synthesis is downstream of integrin activation, or whether it is downstream of an additional, unidentified MMP-9-triggered pathway. In any event, MMP-9 is activated in hippocampus by inhibitory avoidance learning and is required for consolidating memory (47,48). Thus, the cellular plasticity mechanisms we describe here likely underlie the contribution of MMP-9 to cognitive function.…”