PROTEASE INDUCED PLASTICITY: MATRIX METALLOPROTEINASE-1 ACTIVATION OF PROTEASE ACTIVATED RECEPTOR 1 INDUCES NEURONAL STRUCTURAL PLASTICITY

Abstract

The brain continues to change long after development ceases. Structural modifications to mature cells in the brain as well as the integration newborn neurons through adult hippocampal neurogenesis contribute to plasticity found in the healthy brain. Neurological disorders and injury, however, can disrupt proper plasticity processes leading to deleterious outcomes. Elucidating the exact mechanisms of plasticity in varied contexts remains a highly researched topic. The brain is comprised of a complex system of neurons, glia, and other supporting cells. In neurons, modifications can occur on processes that extend from the neuronal cell body (dendrites) as well as tiny membranous protrusions stemming from the dendrites also known as spines. This study reveals how a specific extracellular matrix remodeling protein, matrix metalloproteinase 1 (MMP-1), directs neuronal structure complexity through activation of a G-protein coupled receptor called protease activated receptor 1 (PAR1). MMP-1 mediated activation of PAR1 increases neuronal dendritic arborization, spine number, and increased proliferation of adult neural progenitor cells, which in turn stimulates aberrant behaviors associated with disrupted plasticity in vivo.

Matrix metalloproteinases (MMPs) are a family of secreted endopeptidases expressed by neurons and glia. Regulated MMP activity contributes to physiological synaptic plasticity, while dysregulated activity can stimulate injury. Disentangling the role individual MMPs play in neuroplasticity is difficult due to overlapping structure and function as well as cell-type specific expression. To overcome these challenges, this study uses a novel system to investigate the selective overexpression of MMP-1 in GFAP expressing cells in vivo. More specifically, application of exogenous MMP-1, in vitro, stimulates PAR1 dependent increases in intracellular Ca2+ concentration and dendritic arborization. Overexpression of MMP-1, in vivo, increases dendritic complexity and induces biochemical and behavioral endpoints consistent with increased GPCR signaling. Further, data suggest that activation of the MMP-1/PAR1 axis increases both progenitor cell proliferation and neuronal fate specification in adult neurogenesis. These data are exciting because they demonstrate that an astrocyte-derived protease can influence neuronal plasticity through an extracellular matrix independent mechanism.