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 5

LAMB1 deficiency evokes neuronal hyperexcitability and synaptic potentiation in ACC pyramidal neurons.

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LAMB1 deficiency evokes neuronal hyperexcitability and synaptic potentia...
(A) Whole-cell patch-clamp recording from ACC layer II/III pyramidal neurons. Scale bar: 50 μm. (B) APs induced by current injection at 100 pA in neurons expressing shLamb1 or scrambled shRNA (n = 11–17). (C) Left: I-O curve in response to a depolarizing current step (20 pA step, 500 ms duration) showing a higher firing frequency in mice expressing shLamb1 (n = 11–17). ****P < 0.0001, by Friedman’s M test. Right: Typical result at an intensity of 100 pA. **P < 0.01, by 2-tailed, unpaired separate variance estimation t test. (D) A lowered rheobase was observed after LAMB1 knockdown (n = 8–11). ***P < 0.001, by Mann-Whitney U test. (E and F) Representative traces (E) and I-O curve (F) of AMPAR-mediated eEPSCs following stimulation of layer V/VI ACC pyramidal neurons in mice of both genotypes (n = 16). ****P < 0.0001, by Friedman’s M test (left panel) and Mann-Whitney U test (right panel). Right panel in F shows typical quantification of AMPARs-eEPSCs evoked by 300 μA stimulation. (G and H) Representative traces (G) and quantitative summary (H) of AMPAR/NMDAR EPSC ratios for mice of both genotypes (n = 12–18). ***P < 0.001, by 2-tailed, unpaired t test for AMPARs-eEPSCs; **P < 0.01, by Mann-Whitney U test for NMDAR-eEPSCs and AMPAR/NMDAR. Data are presented as the mean ± SEM. See Supplemental Table 2 for detailed statistical information.