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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Research Article Neuroscience

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 8

LAMB1 knockdown leads to increased AMPAR membrane trafficking and increased activity of ACC pyramidal neurons.

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LAMB1 knockdown leads to increased AMPAR membrane trafficking and increa...
(A and B) Representative immunoblots (A) and quantitative summary (B) showing the expression of AMPARs and NMDAR subunits in the membrane fraction of ACC tissue from mice expressing scrambled shRNA or shLamb1 (n = 3). For the quantitative analysis in B, a 2-step normalization was performed. Step 1: each blot was normalized (i.e., GluR1, GluR2, NR1, NR2A, NR2B, PSD95) to the loading control Flotillin 1 in the scrambled and shLamb1 groups, respectively; step 2: each subunit in the shLamb1 group was normalized to the scrambled group to assess the changes in each subunit. *P < 0.05 and **P < 0.01, by 2-tailed, unpaired t test. (C) Immunofluorescence images showing upregulated PSD95 expression in cultured cortical neurons expressing shLamb1 compared with expression of scrambled shRNA (n = 6). Scale bars: 50 μm and 5 μm (enlarged insets). (D and E) Experimental schematic diagram showing virus injection, optical fiber placement in ACC and behavioral test as well as fiber photometry recording during tail suspension test in mice expressing scrambled shRNA and shLamb1 (n = 6–7). Scale bars: 200 μm and 30 μm (enlarged insets) (E). (F and G) Mechanical threshold (F) and immobility duration (G) in the tail suspension test in mice expressing scrambled shRNA or shLamb1 (n = 6–7). **P < 0.01, by 2-tailed, unpaired t test. (H–J) Representative photometric traces (H) as shown in heatmaps (I) and quantitative summary (J) from 5 independent experiments of peak GCaMP6s signals locked to the onset of struggling. In the heatmaps I, each row in the y axis represents GCaMP6s signals from 5 mice of each group. ****P < 0.0001, by Mann-Whitney U test. Data are presented as the mean ± SEM. See Supplemental Table 2 for detailed statistical information.