The Hippocampal Laminin Matrix Is Dynamic and Critical for Neuronal Survival

Abstract

Laminins are extracellular matrix proteins that participate in neuronal development, survival, and regeneration. During excitotoxin challenge in the mouse hippocampus, neuron interaction with laminin-10 (alpha5,beta1,gamma1) protects against neuronal death. To investigate how laminin is involved in neuronal viability, we infused laminin-1 (alpha1,beta1,gamma1) into the mouse hippocampus. This infusion specifically disrupted the endogenous laminin layer. This disruption was at least partially due to the interaction of the laminin-1 gamma1 chain with endogenous laminin-10, because infusion of anti-laminin gamma1 antibody had the same effect. The disruption of the laminin layer by laminin-1 1) did not require the intact protein because infusion of plasmin-digested laminin-1 gave similar results; 2) was posttranscriptional, because there was no effect on laminin mRNA expression; and 3) occurred in both tPA(-/-) and plasminogen(-/-) mice, indicating that increased plasmin activity was not responsible. Finally, although tPA(-/-) mice are normally resistant to excitotoxin-induced neurodegeneration, disruption of the endogenous laminin layer by laminin-1 or anti-laminin gamma1 antibody renders the tPA(-/-) hippocampal neurons sensitive to kainate. These results demonstrate that neuron interactions with the deposited matrix are not necessarily recapitulated by interactions with soluble components and that the laminin matrix is a dynamic structure amenable to modification by exogenous molecules.

Membrane Localization of Membrane Type 5 Matrix Metalloproteinase by AMPA Receptor Binding Protein and Cleavage of Cadherins

“…Proteinase regulation is particularly important in neurons, which require extensive extracellular remodeling during development and synaptic modification but which rely on ECM adhesion for survival (Chen et al, 2003). To limit proteolysis, extracellular proteinases may be spatially confined and active only at those sites where specific substrates require degradation (Basbaum and Werb, 1996;Seeds et al, 1997).…”

“…The serine proteinase tPA is regulated by synaptic activity and contributes to LTP, axonal elongation, formation of new synapses, and neuronal remodeling (Qian et al, 1993;Gualandris et al, 1996;Huang et al, 1996;Baranes et al, 1998;Madani et al, 1999;Neuhoff et al, 1999). Although the mechanisms are still incompletely understood, they could involve degradation of ECM substrates such as laminin (Chen and Strickland, 1997;Chen et al, 2003), proteoglycans, (Wu et al, 2000), or receptors such as the NMDA receptor (Nicole et al, 2001). …”

“…During CNS development, MMPs facilitate cell migration, myelinogenesis, and axon elongation, mostly through degradation of nonpermissive ECM substrates (Yong et al, 2001). MMPs may also degrade ␤-dystroglycan, laminin, and neurotrophins, which regulate neuronal survival and synapse structure (Lee et al, 2001;Costa et al, 2002;Kaczmarek et al, 2002;Chen et al, 2003).…”

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

“…An additional recent report states that MMP-9 contributes to delayed neuronal cell death in the hippocampus after transient global ischemia (Lee et al, 2004). Although several reports (Asahi et al, 2001;Castellanos et al, 2003;Chen et al, 2003;Hamann, 2003;Horstmann et al, 2003) suggest that basement membrane proteins are involved in an MMP-9 proteolytic pathway, it is unclear how MMP substrates contribute to neuronal cell death. To identify potential targets of MMP-9 proteolysis in ischemic cortex, we examined several basement membrane proteins, including laminin, by immunohistochemistry.…”

Matrix Metalloproteinase 1 Interacts with Neuronal Integrins and Stimulates Dephosphorylation of Akt

“…Although such toxicity may follow from extracellular matrix destruction (14), it is also reasonable to consider the non-mutually exclusive possibility that other mechanisms are involved. One extracellular matrixindependent mechanism by which MMPs may function involves their ability to cleave non-matrix proteins and thereby generate potential cell surface receptor signaling ligands (15)(16)(17)(18)(19).…”