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 8

Ketamine blocks Tiam1-mediated synaptic plasticity in ACC neurons of mouse models of chronic pain.

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Ketamine blocks Tiam1-mediated synaptic plasticity in ACC neurons of mou...
(A and B) Ketamine treatment blocked chronic pain–induced increases in Tiam1 activity in the ACC, as demonstrated by the GST-Rac1G15A affinity-precipitation assay (n = 4 mice for each group). (C) A single subanesthetic dose of ketamine (15 mg/kg) blocked chronic pain–induced increases in the ratio of F-actin to G- actin in the ACC (n = 4 mice for each group). (D and E) Ketamine treatment prevented chronic pain–induced increases in the density of dendritic spines in ACC neurons (sham-saline, n = 25 dendrites from 3 mice; sham-ketamine, n = 25 dendrites from 3 mice; SNI-saline, n = 26 dendrites from 3 mice; SNI-ketamine, n = 30 dendrites from 3 mice). Scale bar: 10 μm. (F and G) Ketamine treatment abolished chronic pain–induced increases in synaptic NMDAR subunit protein levels in the ACC (n = 4 mice for each group). (H and I) Ketamine treatment blocked chronic pain–induced increases in the NMDAR currents elicited by puff application of 100 μM NMDA to ACC pyramid neurons (sham-saline, n = 25 neurons from 4 mice; sham-ketamine, n = 22 neurons from 3 mice; SNI-saline, n = 31 neurons from 4 mice; SNI-ketamine, n = 35 neurons from 4 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 (B, E, and I); 2-tailed unpaired t test (sham versus SNI) (C and G).