Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage

Abstract

Matrix metalloproteinase (MMP)-2 and -9 are pivotal in remodeling many tissues. However, their functions and candidate substrates for brain development are poorly characterized. Intercellular adhesion molecule-5 (ICAM-5; Telencephalin) is a neuronal adhesion molecule that regulates dendritic elongation and spine maturation. We find that ICAM-5 is cleaved from hippocampal neurons when the cells are treated with N-methyl-d-aspartic acid (NMDA) or α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). The cleavage is blocked by MMP-2 and -9 inhibitors and small interfering RNAs. Newborn MMP-2– and MMP-9–deficient mice brains contain more full-length ICAM-5 than wild-type mice. NMDA receptor activation disrupts the actin cytoskeletal association of ICAM-5, which promotes its cleavage. ICAM-5 is mainly located in dendritic filopodia and immature thin spines. MMP inhibitors block the NMDA-induced cleavage of ICAM-5 more efficiently in dendritic shafts than in thin spines. ICAM-5 deficiency causes retraction of thin spine heads in response to NMDA stimulation. Soluble ICAM-5 promotes elongation of dendritic filopodia from wild-type neurons, but not from ICAM-5–deficient neurons. Thus, MMPs are important for ICAM-5–mediated dendritic spine development.

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

“…In addition, the expression and activity of MMP-9 depend on NMDA receptor activation and are associated with LTP development (Meighan et al, 2006;Nagy et al, 2006). Activation of NMDA receptors leads to MMP-mediated modification of cell adhesion molecules and the development of dendritic spines (Tian et al, 2007). Our results suggest that MMP-9 expression and activity are regulated by repetitive activation of NMDA receptors, which may result in remodeling of neuronal circuits, epileptogenesis, and the development of kindling.…”

“…Recent studies have linked MMPs to various pathologic conditions in the central nervous system, including ischemia, multiple sclerosis, Parkinson's disease, malignant glioma, Alzheimer's disease, and epilepsy. Interestingly, some evidence suggests that, in addition to its known extracellular role in macromolecule degradation, MMP may mediate apoptotic and/or necrotic cell death (Jourquin et al, 2003;Kim et al, 2009) and synaptic plasticity (Tian et al, 2007;Wilczynski et al, 2008;Takács et al, 2010). The gelatinases MMP-2 and MMP-9 are initially expressed as inactive proenzymes that are cleaved to their active forms after they are released from cells (Van den Steen et al, 2002), allowing these proteases to regulate the levels of extracellular substrates.…”

“…Interestingly, MMP-9 expression is induced via NMDA receptor signaling (Meighan et al, 2006;Nagy et al, 2006;Tian et al, 2007). Therefore, we investigated the effects of MK-801 on PTZ-induced increases in MMP-9 expression and kindled seizure.…”

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

“…Another study suggests that Wnt signaling can directly mediate co-regulation of heparanase and Mmps (Zcharia et al, 2009). Indeed, both neural activity and intercellular signaling can stimulate Mmpdependent ectodomain shedding of plasma membrane target proteins, thereby directly regulating the surface abundance of HSPGs and receptors, as well as other Mmps, which thus reciprocally modulate intra-and extracellular organization (Dansie and Ethell, 2011;Huntley, 2012;Tian et al, 2007). From this model, the spatial arrangement of Dlp could be affected by co-regulated sheddase activity that is differentially altered in mmp1 and mmp2 mutants.…”

Increased Expression of Matrix Metalloproteinase-9 in Patients with Temporal Lobe Epilepsy

“…It has been reported that the expression and activity of MMP-9 depend on NMDA receptor activation and are associated with LTP development (21,25). Moreover, activation of NMDA receptors leads to MMP mediated modification of cell adhesion molecules and the development of dendritic spines (38). Dendritic spine morphology and synaptic potentiation are dynamically modulated by ECM proteins and cell surface proteins with which they interact.…”