How Ketamine Works
Summary: Chronic pain in mice activates Tiam1 in pyramidal neurons of 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: the 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 that drives these depressive systems, according to a study published in The Journal of Clinical Investigation.The mechanism works to cause 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-leads the research.
“Chronic pain is a major unresolved health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama in Birmingham’s 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 cell cytoskeletons. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to Tiam1 activation in ACC pyramidal neurons, leading to an increase in the number of spines on the neuron. dendrites. Dendrites are treelike appendages attached to the body of a neuron that receives communications from other neurons.
This higher spine density increased the number of connections and the strength of those connections between neurons, a change known as synaptic plasticity. These increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model, using a Tiam1 antagonist, relieved mice of depression and decreased neuron hypersensitivity.
The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism of these symptoms, the team led by Li and Tolias first showed that Tiam1 in ACC was activated in two chronic pain mouse models with depressive or anxious behaviors, compared to controls.
To show that Tiam1 in ACC modulates depression-like behaviors induced by chronic pain, the researchers used molecular scissors to delete Tiam1 from excitatory neurons in the forebrain of mice. These mice were viable and fertile with no significant alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive or anxious behaviors in five different tests that assess depression or anxiety.
When the researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate depression-like behaviors induced by chronic pain.
Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is impaired synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus, and the amygdala.
Li and Tolias found similar changes in ACC dendritic neurons for chronic pain-induced depression-like behavior – they found a significant increase in dendritic spine density and signs of increased construction of the cytoskeleton.
This was accompanied by an increase in NMDA receptor proteins and an increase in NMDA current amplitudes in ACC neurons, both associated with hyperactivity.
These maladaptive changes were not observed in Tiam1-knockout mice.
The researchers further showed that inhibiting Tiam1 signaling with a known inhibitor relieved depression-like behaviors induced by chronic pain, without reducing hypersensitivity to chronic pain itself. Inhibition also normalized dendritic spine density, cytoskeletal construction, NMDA receptor protein levels, and NMDA current amplitudes.
Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in depression induced by chronic pain, without diminishing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias, and colleagues showed that the sustained antidepressant effects of ketamine 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 that Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant effects of ketamine, revealing it as a potential therapeutic target for the treatment of mood disorders. comorbidities in chronic pain,” Li said.
Co-first authors of the study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant 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 and Francisco A. Blanco, and Changqun Yao, Baylor College of Medicine; Juan P. Cata, MD Anderson Cancer Center, Houston, TX; and De-Pei Li, University of Missouri School of Medicine, Columbia, Missouri.
Funding: Support came from U.S. Department of Defense grants W81XWH-20-10790 and W81XWH-21-10742, Mission Connect Foundation/TIRR, and National Institutes of Health grant NS062829.
About this pain and depression research news story
Author: Jeffrey Hansen
Source: the University of Alabama at Birmingham
Contact: Jeffrey Hansen – University of Alabama at Birmingham
Picture: The image is in the public domain
Original research: Open access.
“TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant actions in chronic pain” by Lingyong Li et al. Clinical Investigation Journal
TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant actions in chronic pain
Chronic pain often leads to depression, increasing the patient’s suffering and worsening the prognosis. While anterior cingulate cortex (ACC) hyperactivity appears to be critically implicated, the molecular mechanisms underlying the comorbid depressive symptoms of chronic pain remain elusive. T-cell lymphoma invasion and metastasis 1 (Tiam1) is a guanine nucleotide exchange factor Rac1 (GEF) that promotes the development of dendrites, the spine, and synapses during brain development.
Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin and synaptic cytoskeleton reorganization NOT-stabilization of the methyl-d-aspartate receptor (NMDAR). This Tiam1-coordinated synaptic plasticity underlies ACC hyperactivity and results in depression-like behaviors induced by chronic pain.
Notably, the 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 that Tiam1 is a critical factor in the pathophysiology of depression-like behaviors induced by chronic pain and the sustained antidepressant effects of ketamine.