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How Long-Term Benzodiazepine Use Leads to Cognitive Impairments

FeaturedNeurosciencePsychology

·March 6, 2022

Summary: Mouse study reveals synaptic loss associated with a daily sleep-inducing dose of diazepam for several weeks leads to cognitive impairments. However, the effect was reversible after discontinuing benzodiazepine use.

Source: LMU

Benzodiazepines are effective and widely used drugs for treating states of anxiety and sleep disorders. While short-term treatments are considered safe, their long-term intake can lead to physical dependence and, particularly in the case of older people, to cognitive impairments.

The mechanisms by which benzodiazepines trigger these changes had previously been unknown. Researchers led by Jochen Herms and Mario Dorostkar from LMU’s Center for Neuropathology and Prion Research and the German Center for Neurodegenerative Diseases (DZNE) have now been able to demonstrate in an animal model that the active ingredient leads to the loss of neural connections in the brain.

A key role is played by immune cells of the brain known as microglia. Benzodiazepines bind to a specific protein, the translocator protein (TSPO), on the surface of cell organelles of the microglia. This binding activates the microglia, which then degrade and recycle synapses—that is, the connections between nerve cells.

Experiments carried out by the scientists showed that the synapse loss in mice that had received a daily sleep-inducing dose of the benzodiazepine diazepam for several weeks led to cognitive impairments.

Diazepam alters dendritic spine density and dynamics in vivo. Credit: The researchers

“It was known that microglia play an important role in eliminating synapses both during brain development and in neurodegenerative diseases,” say Dr. Yuan Shi and Mochen Cui, co-authors of the study.

“But what really surprised us was that such well-researched drugs as benzodiazepines influence this process.” When diazepam treatment was discontinued, the effect persisted for some time, but was ultimately reversible.

In the opinion of the researchers, the study could have effects on how sleep disorders and anxiety are treated in people at risk of dementia. “Drugs that are known to have no binding affinity to TSPO should be preferred where possible,” say the authors.

Original Research: Closed access.
“Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)” by Yuan Shi et al. Nature Neuroscience

Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown.

Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material.

Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.

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