Extracellular matrix protein laminin β1 regulates pain sensitivity and anxiodepression-like behaviors in mice
Zhen-Zhen Li, … , Sheng-Xi Wu, Ceng Luo
Zhen-Zhen Li, … , Sheng-Xi Wu, Ceng Luo
Published June 22, 2021
Citation Information: J Clin Invest. 2021;131(15):e146323. https://doi.org/10.1172/JCI146323.
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Extracellular matrix protein laminin β1 regulates pain sensitivity and anxiodepression-like behaviors in mice

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.

Authors

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

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Figure 3

LAMB1 knockdown in the ACC induces pain hypersensitivity and anxiodepression.

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LAMB1 knockdown in the ACC induces pain hypersensitivity and anxiodepres...
(A) Schematic diagram of intra-ACC virus injection into C57BL/6 mice (n = 10). Scale bar: 500 μm. (B and C) Double-immunofluorescence images (B) and Western blots (C) showing efficient LAMB1 knockdown in the ACC (n = 6). ****P < 0.0001, by 2-tailed, unpaired separate variance estimation t test. Scale bars: 200 μm and 70 μm (enlarged insets). (D and E) Stimulus response curve and mechanical threshold showing that ACC LAMB1 knockdown exacerbated ipsilateral mechanical sensitivity in sham-treated (D) and SNI-treated (E) mice (n = 10). ****P < 0.0001, by Mann-Whitney U test. (F) Ipsilateral thermal sensitivity was unaltered by LAMB1 knockdown in the sham- or SNI-treated state (n = 10). ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparison test. (G) Traveling trajectory in the EPM and quantitative summary showed that sham-treated mice expressing shLamb1 traveled shorter distances in the open arm (n = 10). *P < 0.05 and ****P < 0.0001, by Kruskal-Wallis H test with Nemenyi’s multiple-comparison test. (H) The TST showed that expression of AAV-shLamb1 resulted in longer immobility for the sham-treated mice and further exacerbated immobility following SNI (n = 10). *P < 0.05 and **P < 0.01, by Kruskal-Wallis H test with Nemenyi’s multiple-comparison test. (I) The SPT showed a strong reduction in sucrose preference in shLamb1-expressing mice (n = 10). **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparison test. Data are presented as the mean ± SEM. See Supplemental Table 2 for detailed statistical information. PWMT, paw withdrawal mechanical threshold; PWTL, paw withdrawal thermal latency.