Summary: Study unveils a possible mechanism by which anxiolytics act on the brain and lead to cognitive impairment.
ANSTO Health researchers contributed to an international study published in nature neuroscience It sheds light on the mechanism by which anti-anxiety drugs act on the brain, which can lead to cognitive impairment in susceptible individuals.
The research relies critically on a unique laboratory model developed at ANSTO known as the “Guwiang Vura TSPO knockout” (a healthy mouse lacking an evolutionary ancient protein normally present in mitochondria). It is the organ that provides energy to a cell. Because of the protein’s importance for energy production, it is called Guviang Wurra (“fire mouse”) in the Dharaval language.
The study suggested that the anti-anxiety drug didn’t act directly on nerve cells, but rather on microglial cells (cells in the brain’s internal immune system that can cluster around nerve cells and their connections, synapses). and the movement of microglial cells disrupted dendritic spines (small projections of neurons that have synaptic connections to other nerve cells at the ends).
“This observation is important because long-term use of anti-anxiety drugs has been thought to help accelerate dementia and it was not known how this might come about,” said ANSTO co-author Professor Richard Bunty.
“The knowledge gained in this work from a large international team aids in the development of anti-anxiety drugs without such deleterious cognitive effects. The specific experiment looked closely at how long-term use of anti-anxiety drugs like diazepam can alter the brain’s complex wiring.
“We have neurons and each neuron is connected to another neuron called a synapse. Here the research team recognized the importance of other neighboring cells, the microglial cells.
“These are small and highly mobile cells that are part of the non-neuronal matrix in which nerve cells are embedded. This matrix makes up a large part of the brain and actually directly affects the functioning of neural networks. The compound studied, diazepam, did not go directly to the long spine and synaptic connections between nerve cells, but to microglia.
“In this way, the drug altered the normal activity of microglial cells and indirectly the maintenance function that microglia have in synaptic nerve cell connections. It is interesting to see how the brain’s local immune system, which includes microglial cells, is directly involved in the overall functional integrity of the brain.
There are a number of serious disease states such as dementia, but also in particular those often characterized by extreme or prolonged fatigue such as we now see in “prolonged COVID” or following accidental or medical exposure to radiation where we know that the immune system is very responsive strong.
“When the activity of microglial cells disrupts the connections between neurons, it’s almost as if neural connections are severed, and this would explain how subtle changes can drive the further progression of dementia, or speculatively – severe exhaustion” may become the reason .
“For me, the conceptual importance of the work is that it shows us that we want to see the brain not just as a switchboard with point-to-point connections, but as a switchboard in an unusual environment. “
Credit: ANSTO News
You can think of the collective movement of microglial cells as similar to a lava lamp. Microglial cells form amorphous but still localized dynamics, like bubbles that move up and down when excited by heat.
And this ever-changing local activity can disrupt more stable cable connections, which in extreme cases may be smaller than the local cable melt that affects an overall system that otherwise looks fine.
The overlap of the immune system (glial cells) and the nervous system (neurons) is important for understanding the underlying cellular mechanisms.
The overlap of the immune system (glial cells) and the nervous system (neurons) is important for understanding the underlying cellular mechanisms. Image is in the public domain
Both systems mediate between the inner world of the organism and the input from the environment. This self/non-self interaction manifests itself in a dynamic equilibrium in which connections are formed by the nervous system and modified or even dissociated by cells of the immune system.
“Using the potent TSPO knockout mouse model provided evidence that the mitochondrial protein TSPO was involved in dendritic junction remodeling by microglial cells. Anti-anxiety drugs like diazepam bind to TSPO.
“In a genetically engineered animal like the TSPO knockout mouse, the side effects described for diazepam simply do not occur. Diazepam administered to the laboratory model showed a reduction in dendritic spines, while the TSPO knockout model did not show these defects,” Pro. Banti said.
Based on the results, the authors concluded that TSPO-mediated dendritic spine impairment as a result of anti-anxiety drug (benzodiazepine) use accelerated cognitive decline.
It is also possible that the chronic intake of drugs such as benzodiazepines changes the function of microglial cells, which can promote disease-specific pathological changes in the brain.
About this news from psychopharmacology research
Author: press office
Contact: Press Office – ANSTO
Picture: Image is in the public domain
basic research: closed access.
“Long-term treatment with diazepam lengthens microglial spinal cord and reduces cognitive performance through mitochondrial 18 kDa translocator protein (TSPO)” by Yuan Shi et al. nature neuroscience
Long-term treatment with diazepam elongates the microglial backbone and decreases cognitive performance through the 18-kDa mitochondrial translocator protein (TSPO).
Benzodiazepines are commonly prescribed medications used to treat anxiety and insomnia. In addition to the development of tolerance and a tendency to abuse, their chronic use can lead to cognitive impairment and an increased risk of dementia. However, the mechanism by which benzodiazepines may contribute to persistent cognitive decline is still unknown.
Here we report that diazepam, a commonly prescribed benzodiazepine, disrupts the structural plasticity of dendritic spines, leading to cognitive impairment in rats. Diazepam induces these defects through the 18 kDa mitochondrial translocator protein (TSPO) and not through classic aminobutyric acid type A receptors, which alter microglial morphology and phagocytosis of synaptic material.
Overall, our results demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and consequently cause cognitive impairment.