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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-08, Vol.131 (15), p.1-21
Main Authors: Li, Zhen-Zhen, Han, Wen-Juan, Sun, Zhi-Chuan, Chen, Yun, Sun, Jun-Yi, Cai, Guo-Hong, Liu, Wan-Neng, Wang, Tao-Zhi, Xie, Yang-Dan, Mao, Hong-Hui, Wang, Fei, Ma, Sui-Bin, Wang, Fu-Dong, Xie, Rou-Gang, Wu, Sheng-Xi, Luo, Ceng
Format: Article
Language:English
Subjects:
Actin
Alzheimer's disease
Anxiety
Behavior
Biomedical research
Cofilin
Comorbidity
Cortex (cingulate)
Emotions
Extracellular matrix
Functional plasticity
Hypersensitivity
Intracellular
Intracellular signalling
Kinases
Laminin
Matrix protein
Mental depression
Mental disorders
Neurotransmitter release
Pain
Pain perception
Peripheral neuropathy
Proteins
Pyramidal cells
RhoA protein
Signal transduction
Structure-function relationships
Therapeutic targets
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Summary: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 a-, one ß-, and one у-chain and is implicated in several pathophysiological processes. Here, we showed in mice that laminin ß1 (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 ß1 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 ß1 signaling as a promising therapeutic target for the treatment of neuropathic pain and associated anxiodepression.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI146323