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bioRxiv · 10.1101/2021.10.15.464592

Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain

Ru, Q.·Lu, Y.·Saifullah, A. B.·Blanco, F. A.·Yao, C.·Cata, J. P.·Li, D.-P.·Tolias, K. F.·Li, L.
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Abstract

Hyperactivity in the anterior cingulate cortex (ACC) drives comorbid depressive symptoms in chronic pain, but the cause of ACC hyperactivity is currently unclear. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, induces rapid and sustained antidepressant-like effects in chronic pain-induced depression in both patients and animal models. However, the mechanisms underlying ketamines sustained antidepressant effects remain elusive. Here, we show that Tiam1, a Rac1-specific guanine nucleotide exchange factor (GEF) that was previously identified as a critical mediator of NMDAR-dependent dendritic spine development, is activated in the ACC in chronic pain mice displaying depressive-like behaviors. Conditional deletion of Tiam1 from postnatal forebrain excitatory neurons, specific deletion of Tiam1 from ACC neurons, or pharmacological inhibition of the Tiam1-Rac1 signaling pathway prevents chronic pain-induced depressive-like behaviors in mice. Biochemical, morphological, and electrophysiological assays reveal that Tiam1 orchestrates synaptic structural and functional remodeling in ACC neurons via actin cytoskeleton reorganization and synaptic NMDAR stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Ketamine induces sustained antidepressant effects in chronic pain by blocking Tiam1-mediated synaptic structural and functional plasticity in ACC neurons. Our results reveal Tiam1 as a key factor in the pathophysiology of chronic pain-induced depression and in the sustained antidepressant effects of ketamine in ACC neurons. These findings highlight Tiam1 as a potential therapeutic target for the treatment of comorbid depressive symptoms in chronic pain.

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Ru, Q., Lu, Y., Saifullah, A. B., Blanco, F. A., Yao, C., Cata, J. P., Li, D.-P., Tolias, K. F., Li, L.. 2021-10-16. Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain. https://doi.org/10.1101/2021.10.15.464592

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