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 3

Tiam1 deletion from ACC neurons prevents chronic pain–induced depressive-like behaviors.

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Tiam1 deletion from ACC neurons prevents chronic pain–induced depressive...
(A) Experimental paradigm. (B) Representative image of the ACC after bilateral injections of rAAV8 (1 μl/site) expressing GFP. (C) Western blot analysis showing Cre-mediated Tiam1 loss in the ACC of Tiam1-floxed mice (n = 6 mice for each group). (D) Time course of pain hypersensitivity in response to von Frey filament stimuli in rAAV8-GFP– and rAAV8-Cre-GFP–injected Tiam1-floxed mice before and during the 8 weeks following sham or SNI surgery (GFP-sham, n = 12 mice; GFP-SNI, n = 11 mice; Cre-sham, n = 11 mice; Cre-SNI, n = 11 mice). (E–I) Behavioral tests demonstrating that Tiam1 deletion from ACC neurons prevented depressive-like behaviors in FST (E) and TST (F), but did not change anxiety-like behaviors in EPM (G) or OFA (H) tests or locomotor activity in OFA test (I) in mice with neuropathic pain (7 weeks after surgery) (GFP-sham, n = 12 mice; GFP-SNI, n = 11 mice; Cre-sham, n = 11 mice; Cre-SNI, n = 11 mice). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Two-tailed unpaired t test (C), 2-way ANOVA followed by Tukey’s post hoc test (D–I).