Matrix Metalloproteinase 9 (MMP-9) in Learning and Memory

Abstract

Matrix metalloproteinase 9 (MMP-9) is a protein only recently recognized as pivotal for neuronal plasticity, learning, and memory. MMP-9, together with its endogenous inhibitor TIMP-1, compose a perisynaptically operating enzymatic system involved in the dynamic remodeling of the extracellular matrix via cleavage of numerous extracellular substrates, including growth factor precursors, cell surface receptors, and adhesion molecules. In this chapter we present an overview of the data available on MMP-9 involvement in long term potentiation (LTP, a model of neuronal plasticity), learning and memory. The data show that MMP-9 is required for formation of late LTP, although not in all pathways that were studied. Moreover, MMP-9 activation in specific brain structures following learning of different behavioral tasks has been shown. Studies with inhibitors and genetic ablation of MMP-9 demonstrate that it contributes to the mechanisms underlying memory formation. However, its involvement differ between the tasks with respect to the anatomical location and the temporal pattern, suggesting specific role of MMP-9 in learning and memory. In particular, MMP-9 has been found indispensable for appetitive and spatial memory formation, whereas aversive learning was normal in mice missing MMP-9 activity. Notably, hippocampal LTP (implicated in spatial learning) was disturbed by MMP-9 inhibition, similarly to LTP evoked in the basal and central nuclei of the amygdala, supposedly supporting appetitive memory. In contrast, no deficit in lateral amygdala LTP was observed under conditions of impaired MMP-9 activity. Thus, an interesting avenue of research arises and a more detailed investigation of various molecular mechanisms operating within various brain structures is required.