Overview: Chronic pain in mice activates Tiam1 in pyramidal neurons in the anterior cingulate cortex, increasing the number of dendritic spines and inducing synaptic plasticity. The antidepressant effect of ketamine in chronic pain is mediated by the drug blocking Tiam1-dependent maladaptive synaptic plasticity in ACC neurons.
Source: University of Alabama at Birmingham
Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Now, for the first time, researchers have uncovered the underlying mechanism driving these depressive systems, according to a study published in The Journal of Clinical Research.
The mechanism works to trigger hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for treating chronic pain-induced depression, says Lingyong Li, Ph.D ., and Kimberley Tolias, Ph.D., co-leaders of the study.
“Chronic pain is an important, unmet health problem that affects quality of life,” said Li, an associate professor at the University of Alabama in the Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients with chronic pain have limited effective treatment options.”
The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or break down cells’ cytoskeletons. In particular, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that in a mouse model, chronic pain leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to a neuron’s body that receive communications from other neurons.
This higher spine density increased the number and strength of those connections between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of compounds in the model, by using an antagonist of Tiam1, relieved the mice of depression and reduced neuronal hypersensitivity.
The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 was activated in the ACC in two mouse models of chronic pain with depressive or anxiety-like behaviors, compared to controls.
To show that Tiam1 in the ACC modulates chronic pain-induced depressive behavior, the researchers used molecular scissors to remove Tiam1 from the excitatory neurons of the mice’s forebrains. These mice were viable and fertile, showed no major changes, and still showed hypersensitivity to chronic pain. Remarkably, however, these Tiam1 conditional knockout mice showed no depressive or anxiety-like behaviors in five different tests measuring depression or anxiety.
When researchers specifically removed Tiam1 from ACC neurons, they found the same results as the wider forebrain removal. Thus, Tiam1, expressed in ACC neurons, appears to specifically mediate chronic pain-induced depressive behavior.
Other studies have found that an underlying cause of stress-induced depression and anxiety disorders are changes in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, hippocampus, and amygdala.
Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive behavior – they saw a significant increase in dendritic spine density and signs of increased cytoskeleton formation.
This was associated with increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.
These maladaptive changes were not seen in the Tiam1 knockout mice.
Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated depressive behaviors induced by chronic pain, without reducing hypersensitivity to chronic pain itself. The inhibition also normalized dendritic spine density, cytoskeletal architecture, NMDA receptor protein levels, and NMDA current amplitudes.
Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without reducing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s persistent antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine blocking Tiam1-dependent, maladaptive synaptic plasticity in mouse ACC neurons.
“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the persistent antidepressant-like effects of ketamine, revealing it to be a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said. .
Co-first authors of the study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain,” are Qin Ru and Yungang Lu, Baylor College of Medicine.
Co-authors with Li, Tolias, Ru, and Lu are Ali Bin Saifullah, Francisco A. Blanco, and Changqun Yao, Baylor College of Medicine; Juan P. Cata, MD Anderson Cancer Center, Houston, Texas; and De-Pei Li, University of Missouri School of Medicine, Columbia, Missouri.
financing: The support came from U.S. Department of Defense grants W81XWH-20-10790 and W81XWH-21-10742, the Mission Connect/TIRR Foundation, and the National Institutes of Health grant NS062829.
About this pain and depression research news
Writer: Jeffrey Hansen
Source: University of Alabama at Birmingham
Contact: Jeffrey Hansen – University of Alabama at Birmingham
Image: The image is in the public domain
Original research: Open access.
“TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain” by Lingyong Li et al. Journal of Clinical Research
TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain
Chronic pain often leads to depression, which increases the patient’s suffering and worsens the prognosis. Although 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 reorganization of the actin cytoskeleton and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity supports ACC hyperactivity and stimulates chronic pain-induced depressive behaviors.
Specifically, low-dose administration of 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 that Tiam1 is a critical factor in the pathophysiology of chronic pain-induced depressive behaviors and the persistent antidepressant-like effects of ketamine.