Hippocampal Extracellular Matrix Protein Laminin β1 Regulates Neuropathic Pain and Pain-Related Cognitive Impairment.
10.1007/s12264-025-01422-3
- Author:
Ying-Chun LI
1
;
Pei-Yang LIU
2
;
Hai-Tao LI
2
;
Shuai WANG
2
;
Yun-Xin SHI
2
;
Zhen-Zhen LI
2
;
Wen-Guang CHU
2
;
Xia LI
2
;
Wan-Neng LIU
2
;
Xing-Xing ZHENG
1
;
Fei WANG
2
;
Wen-Juan HAN
2
;
Jie ZHANG
3
;
Sheng-Xi WU
2
;
Rou-Gang XIE
4
;
Ceng LUO
5
Author Information
1. College of Life Sciences, Northwest University, Xi'an, 710069, China.
2. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
3. Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China.
4. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. rgxie@fmmu.edu.cn.
5. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China. luoceng@fmmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Cognitive impairment;
Dorsal hippocampus;
Extracellular matrix;
Laminin β1;
Neuropathic pain
- MeSH:
Animals;
Laminin/genetics*;
Hippocampus/metabolism*;
Neuralgia/metabolism*;
Cognitive Dysfunction/etiology*;
Male;
Peripheral Nerve Injuries/metabolism*;
Extracellular Matrix/metabolism*;
Integrin beta1/metabolism*;
Pyramidal Cells/metabolism*;
Signal Transduction
- From:
Neuroscience Bulletin
2025;41(12):2127-2147
- CountryChina
- Language:English
-
Abstract:
Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca2+ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
