The hippocampal extracellular matrix regulates pain and memory after injury

Maral Tajerian,Ting-Ting Huang,Victor Hung,Gail Lee,Simon Xie,J David Clark,Huy Nguyen,Andrey Victorovich Malkovskiy,Lydia-Marie Joubert,Bende Zou

doi:10.1038/s41380-018-0209-z

Abstract

Chronic pain poses a heavy burden for the individual and society, comprising personal suffering, comorbid psychiatric symptoms, cognitive decline, and disability. Treatment options are poor due in large part to pain centralization, where an initial injury can result in lasting CNS maladaptations. Hippocampal cellular plasticity in chronic pain has become a focus of study due to its roles in cognition, memory, and the experience of pain itself. However, the extracellular alterations that parallel and facilitate changes in hippocampal function have not been addressed to date. Here we show structural and biochemical plasticity in the hippocampal extracellular matrix (ECM) that is linked to behavioral, cellular, and synaptic changes in a mouse model of chronic pain. Specifically, we report deficits in working location memory that are associated with decreased hippocampal dendritic complexity, altered ECM microarchitecture, decreased ECM rigidity, and changes in the levels of key ECM components and enzymes, including increased levels of MMP8. We also report aberrations in long-term potentiation (LTP) and a loss of inhibitory interneuron perineuronal ECM nets, potentially accounting for the aberrations in LTP. Finally, we demonstrate that MMP8 is upregulated after injury and that its genetic downregulation normalizes the behavioral, electrophysiological, and extracellular alterations. By linking specific extracellular changes to the chronic pain phenotype, we provide a novel mechanistic understanding of pain centralization that provides new targets for the treatment of chronic pain.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.University, Stanford, CA, USA 5 Department of Biology, Stanford University, Stanford, CA, USA 6 Cell Sciences Imaging Facility, Stanford University, Stanford, CA, USA 7 Department of Biomaterials and Advanced Drug Delivery, Stanford University, Stanford, CA, USA 8 AfaSci Research Laboratories, Mountainview, CA, USAChronic pain (CP) is characterized by changes in nociception, affect, and cognition [1, 2] and is often resistant to classical treatment partly due to comorbid maladaptive plastic changes in the central nervous system (CNS) [3,4,5,6,7]
We show structural and biochemical alterations in the hippocampal extracellular matrix (ECM) that are linked to pain, cognitive dysfunction, and cellular plasticity in a mouse model of CP
We report a constellation of deficits in working and location memory that are associated with decreased dendritic complexity, altered ECM microarchitecture, decreased ECM rigidity, and dysregulated ECM remodeling

Summary

Introduction

Despite interest in the role of hippocampal remodeling in CP, experimental efforts far have been focused on cellular mechanisms of plasticity rather than the extracellular environment in which these cells function. This is likely due to both the neuro-centric nature of pain research and the technical difficulties of studying extracellular components. We show an amelioration of these maladaptive behavioral and physiological/biochemical phenotypes following an intervention to normalize ECM imbalance These results delineate extracellular mechanisms of pain-related brain plasticity, thereby offering new therapeutic targets that could modulate already established CNS alterations present in CP

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