Extracellular matrix protein laminin β1 regulates pain sensitivity and anxiodepression-like behaviors in mice.

Zhen-Zhen Li,Rou-Gang Xie,Wan-Neng Liu,Zhi-Chuan Sun,Fu-Dong Wang,Sheng-Xi Wu,Sui-Bin Ma,Fei Wang,Guo-Hong Cai,Wen-Juan Han,Hong-Hui Mao,Ceng Luo,Yun Chen,Jun-Yi Sun,Tao-Zhi Wang,Yang-Dan Xie

doi:10.1172/jci146323

Abstract

Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion. However, substantial efforts have thus far been focused on the intracellular mechanisms of plasticity rather than the extracellular alterations that might trigger and facilitate intracellular changes. Laminin, a key element of the extracellular matrix (ECM), consists of one α-, one β-, and one γ-chain and is implicated in several pathophysiological processes. Here, we showed in mice that laminin β1 (LAMB1) in the ACC was significantly downregulated upon peripheral neuropathy. Knockdown of LAMB1 in the ACC exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 caused actin dysregulation via interaction with integrin β1 and the subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrated the structural and functional plasticity of pyramidal neurons and eventually resulted in pain hypersensitivity and anxiodepression. This study sheds new light on the functional capability of ECM LAMB1 in modulating pain plasticity and identifies a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin β1 signaling as a promising therapeutic target for the treatment of neuropathic pain and associated anxiodepression.

Highlights

Neuropathic pain is frequently comorbid with psychiatric disorders, such as anxiety and depression, rendering it more resistant to classical treatment [1,2,3,4]
LAMB1, an extracellular matrix (ECM) component and previously known to be involved in several physiopathological processes, showed significant transcriptional downregulation following spared nerve injury (SNI) (Figure 1C). We further verified this at the mRNA and protein levels by quantitative real-time PCR and Western blotting in the contralateral anterior cingulate cortex (ACC) at different time points after SNI, with significant downregulation of LAMB1 observed on days 28–56 after SNI (Figure 1, D and E)
F and G, the AMPA-induced (50 μM) current in pyramidal neurons was significantly enhanced by knockdown of LAMB1, whereas the NMDA-induced (50 μM) current was not (Figure 6, F and G). These results suggest that LAMB1 deficiency potentiates synaptic transmission via both presynaptic and postsynaptic mechanisms that likely involve an increase in presynaptic transmitter release probability and responsiveness of postsynaptic AMPARs

Summary

Introduction

Neuropathic pain is frequently comorbid with psychiatric disorders, such as anxiety and depression, rendering it more resistant to classical treatment [1,2,3,4]. Neurons in the ACC are activated by nerve injury, and inhibition of central plasticity in the ACC produces analgesic as well as anxiolytic and antidepressive effects [12,13,14,15,16,17]. Despite these advances, mounting efforts have far been focused on intracellular mechanisms of plasticity rather than the extracellular alterations that might trigger and facilitate intracellular changes in these cellular functions. The extracellular matrix (ECM) is known to provide a supporting scaffold for cells and a unique class of first messengers acting on the adhesion receptors, which in turn can modulate cell functions in response to environmental changes, i.e., nox-

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