TIAM1-mediated synaptic plasticity underlies comorbid depression–like and ketamine antidepressant–like actions in chronic pain
Qin Ru, … , Kimberley F. Tolias, Lingyong Li
Qin Ru, … , Kimberley F. Tolias, Lingyong Li
Published December 15, 2022
Citation Information: J Clin Invest. 2022;132(24):e158545. https://doi.org/10.1172/JCI158545.
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Research Article Neuroscience

TIAM1-mediated synaptic plasticity underlies comorbid depression–like and ketamine antidepressant–like actions in chronic pain

Abstract

Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain–induced depressive-like behaviors. Notably, administration of low-dose ketamine, an NMDAR antagonist emerging as a promising treatment for chronic pain and depression, induces sustained antidepressant-like effects in mouse models of chronic pain by blocking Tiam1-mediated maladaptive synaptic plasticity in ACC neurons. Our results reveal Tiam1 as a critical factor in the pathophysiology of chronic pain–induced depressive-like behaviors and the sustained antidepressant-like effects of ketamine.

Authors

Qin Ru, Yungang Lu, Ali Bin Saifullah, Francisco A. Blanco, Changqun Yao, Juan P. Cata, De-Pei Li, Kimberley F. Tolias, Lingyong Li

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Figure 2

Conditional deletion of Tiam1 from postnatal forebrain excitatory neurons prevents chronic pain–induced depressive/anxiety-like behaviors.

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Conditional deletion of Tiam1 from postnatal forebrain excitatory neuron...
(A and B) Time course of SNI-induced pain reflexive behavior, demonstrated by a von Frey mechanical threshold assay (A, control-sham [Ctrl-sham], n = 5 mice; Ctrl-SNI, n = 5 mice; cKO-sham, n = 7 mice; cKO-SNI, n = 7 mice) and pain affective-motivational behavior in response to acetone evaporation (B, n = 9 mice for each group) in control and Tiam1-cKO mice before and during the 8 weeks following surgery. (C) Escape latency from white-lit chamber in the MCA with 5 mm probe height in the conflict chamber 7 weeks after sham or SNI surgery (Ctrl-sham, n = 10 mice; Ctrl-SNI, n = 10 mice; cKO-sham, n = 12 mice; cKO-SNI, n = 12 mice). (D–H) Behavioral tests demonstrating that chronic neuropathic pain (7 weeks after SNI surgery) induced depressive/anxiety-like behaviors in control mice, but not in Tiam1-cKO mice, in the FST (D), TST (E), SPT (F) and EPM (G) and OFA (H) tests (Ctrl-sham, n = 8 mice; Ctrl-SNI, n = 8 mice; cKO-sham, n = 7 mice; cKO-SNI, n = 8 mice; FST). (I) OFA showing that chronic neuropathic pain had no effect on locomotion in control or Tiam1-cKO mice (n = 7-8 mice). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Two-way ANOVA followed by Tukey’s post hoc test (A, B, D–I); 1-way ANOVA followed by Tukey’s post hoc test (C).