TIAM1-mediated synaptic plasticity underlies comorbid depression–like and ketamine antidepressant–like actions in chronic pain
Q. Ru, Yungang Lu, Ali Bin Saifullah, Francisco A. Blanco, Changqun Yao, J. Cata, Defa Li, K. Tolias, Lingyong Li
Journal of Clinical Investigation December 15, 2022 DOI: 10.1172/jci158545 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mouse models of chronic pain |
| Intervention | Ketamine |
| Dose | low-dose |
| Topics | Depression Esketamine Ketamine Neuroplasticity |
| Key points | Tiam1 orchestrates synaptic plasticity in ACC neurons that drives depressive-like behaviors in chronic pain, and low-dose ketamine reverses these effects by blocking Tiam1-mediated changes. |
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.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 7
- Chronic Neuropathic Pain and Comorbid Depression Syndrome: From Neural Circuit Mechanisms to Treatment. ACS Chemical Neuroscience July 3, 2024
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity Cell Death Discovery May 1, 2024
- Esketamine reduces postoperative depression in breast cancer through TREK-1 channel inhibition and neurotransmitter modulation. Cancer cell international February 18, 2025
- Esketamine alleviates the pain-depression dyad: insights from exploratory transcriptomic profiling and Wnt4-associated molecular alterations within the anterior cingulate cortex Frontiers in Pharmacology October 16, 2026
and 2 more in the library
Cites 5
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Anesthesiology October 1, 2011
- Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway. Progress in Neuro-Psychopharmacology and Biological Psychiatry February 25, 2020
- Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 1, 2008