Tiam1 Coordinates Synaptic Structural and Functional Plasticity Underpinning the Pathophysiology of Neuropathic Pain

Authors

Lingyong Li
Qin Ru
Yungang Lu
Xing Fang
Guanxing Chen
Ali Bin Saifullah
Changqun Yao
Kimberley F Tolias

Publication Date

7-5-2023

Journal

Neuron

DOI

10.1016/j.neuron.2023.04.010

PMID

37146610

PMCID

PMC10330505

PubMedCentral® Posted Date

7-5-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Chronic Pain, Guanine Nucleotide Exchange Factors, Neuronal Plasticity, Actins, Neuralgia

Abstract

Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the initiation, transition, and maintenance of neuropathic pain. Furthermore, an antisense oligonucleotides (ASO) targeting spinal Tiam1 persistently alleviate neuropathic pain sensitivity. Our findings suggest that Tiam1-coordinated synaptic functional and structural plasticity underlies the pathophysiology of neuropathic pain and that intervention of Tiam1-mediated maladaptive synaptic plasticity has long-lasting consequences in neuropathic pain management.

Current treatment options for neuropathic pain are limited. In this study, Li et al. identify Tiam1-coordinated maladaptive synaptic structural and functional plasticity in spinal excitatory neurons as the pathophysiological mechanism that initiates, transits, and sustains neuropathic pain, thus providing a promising therapeutic target to treat neuropathic pain effectively.

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