Matrix Metalloproteinase-9 Undergoes Expression and Activation during Dendritic Remodeling in Adult Hippocampus

Abstract

Neurons of adult brain are able to remodel their synaptic connections in response to various stimuli. Modifications of the peridendritic environment, including the extracellular matrix, are likely to play a role during synapse remodeling. Proteolytic disassembly of ECM is a complex process using the regulated actions of specific extracellular proteinases. One of bestcharacterized families of matrix-modifying enzymes is the matrix metalloproteinase (MMP) family. Here, we describe changes in the expression and function of two well known MMPs, MMP-9 and MMP-2, in adult rat brain before and after systemic administration of the glutamate receptor agonist kainate. Kainate application results in enhanced synaptic transmission and seizures followed by selective tissue remodeling, primarily in hippocampal dentate gyrus. MMP-9 but not MMP-2 was highly expressed by neurons in normal adult rat brain. MMP-9 protein was localized in neuronal cell bodies and dendrites. Kainate upregulated the level of MMP-9 mRNA and protein within hours after drug administration. This was followed several hours later by MMP-9 enzymatic activation. Within hippocampus, MMP-9 mRNA and activity were increased selectively in dentate gyrus, including its dendritic layer. In addition, MMP-9 mRNA levels decreased in areas undergoing neuronal cell loss. This unique spatiotemporal pattern of MMP-9 expression suggests its involvement in activity-dependent remodeling of dendritic architecture with possible effects on synaptic physiology.

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

“…NMDA receptors are required for such activation, but the downstream steps that then lead to MMP activation remain unknown and presumably account for some delay. It is conceivable that the onset of MMP-9 proteolysis could occur sooner, because pro-MMP-9 is present within the neuropil (10,36) and could in theory be quickly activated by signaling molecules such as nitric oxide (37) or BDNF (38) that are released by LTP induction (39).…”

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

“…The brains were sectioned at a thickness of 20 m in a cryostat. We adapted a previously published in situ zymography method to localize net gelatinolytic activity in brain sections (Szklarczyk et al, 2002). Unfixed sections were incubated for 24 h at 37°C in a humid dark chamber with reaction buffer containing 0.5 M Tris-HCl (pH 7.6), 1.5 M NaCl, 50 mM CaCl 2 , 2 mM NaN 3 , and 100 g/ml intramolecularly quenched FITC-labeled DQ-gelatin (Invitrogen).…”

“…Gelatinases (MMP-2 and MMP-9), for example, cleave the cell adhesion proteins collagen IV and V, laminin, and chondroi-tin sulfate proteoglycan (Yong et al, 2001). Of clinical relevance, MMP-9 has been implicated in amyloid-induced cognitive impairment and neurotoxicity (Mizoguchi et al, 2009), cerebral ischemia, kainate-induced neuronal injury (Szklarczyk et al, 2002), hippocampal long-term potentiation and memory (Nagy et al, 2006), and methamphetamine dependence (Mizoguchi et al, 2007a(Mizoguchi et al, , 2007b. Thus, MMP-9 is involved in neuronal activitydependent synaptic plasticity and cell death in the brain.…”

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

“…By facilitating the access of immunerelated cells in and out of the optic nerve head and retina, a defect in blood-eye barrier may be associated with the involvement of immune system in glaucoma . In addition, matrix metalloproteinases play a regulatory role in axon pathfinding (Nordstrom et al, 1995), and remodeling and integrity of synapses (Bilousova et al, 2006;Kim et al, 2005;Leone et al, 2005) and dendritic architecture (Szklarczyk et al, 2002) after neuronal injury. However, whether oxidative stress-regulated matrix metalloproteinases participate in determining the functional status of the optic nerve during glaucomatous neurodegeneration is currently unknown.…”