Hippocampal Extracellular Matrix Protein Laminin β1 Regulates Neuropathic Pain and Pain-Related Cognitive Impairment
Ying‑Chun Li1,2 · Pei‑Yang Liu2,3 · Hai‑Tao Li2,4 · Shuai Wang2,5 · Yun‑Xin Shi2 · Zhen‑Zhen Li2 · Wen‑Guang Chu2 · Xia Li2,6 · Wan‑Neng Liu2 · Xing‑Xing Zheng1,2 · Fei Wang2 · Wen‑Juan Han2 · Jie Zhang7 · Sheng‑Xi Wu2 · Rou‑Gang Xie2 · Ceng Luo2,81 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 School of Life Science & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conservation & Utilization of Regional Biological Resources, Yanan University, Yanan 716000, China
4 The Fourteenth Squadron of the Fourth Regiment, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
5 The Second Squadron of the First Regiment, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
6 Center for Translational Medicine Research on Sensory-Motor Diseases, Yanan University, Yanan 716000, China
7 Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen 361102, China
8 Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
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.
Keywords
Neuropathic pain; Extracellular matrix; Laminin β1; Dorsal hippocampus; Cognitive impairment
