Neuron with extensions (blue) and microglia cells (red) interacting with synapses. Credit: Y. Shi and M. Cui

Long-Term Benzodiazepine Use Attacks Synapses

Long-term use of benzodiazepines has been linked to cognitive deficits according to Ludwig Maximilian University Of Munich (LMU) researchers.

Benzodiazepines are a class of medications that are used to treat anxiety and sleep disorders. While short-term treatments are typically safe, long-term use may develop into physical dependency and, in the case of the elderly, cognitive problems. Previously, the mechanisms by which benzodiazepines cause these alterations were unclear. Prof. Jochen Herms and Dr. Mario Dorostkar of LMU’s Center for Neuropathology and Prion Research and the German Center for Neurodegenerative Diseases (DZNE) have now shown that the active ingredient causes the breakdown of neural connections in the brain in an animal model.

Microglia, which are brain immune cells, play an important function. Benzodiazepines attach to a particular protein on the surface of microglia cell organelles called the translocator protein (TSPO). The microglia are activated as a result of this binding. This causes them to break down and recycle synapses, which are the connections between nerve cells. Experiments conducted by the researchers revealed that synapse loss in mice that were given a daily sleep-inducing dosage of the benzodiazepine diazepam for several weeks resulted in cognitive deficits.

“It was known that microglia play an important role in eliminating synapses both during brain development and in neurodegenerative diseases,” said 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 medication was stopped, the effects lingered for a while but were eventually reversed.

The findings, according to the researchers, could have an impact on how sleep difficulties and anxiety are managed in patients that could have dementia. The authors state “Drugs that are known to have no binding affinity to TSPO should be preferred where possible.”

Reference: “Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)” by Yuan Shi, Mochen Cui, Katharina Ochs, Matthias Brendel, Felix L. Strübing, Nils Briel, Florian Eckenweber, Chengyu Zou, Richard B. Banati, Guo-Jun Liu, Ryan J. Middleton, Rainer Rupprecht, Uwe Rudolph, Hanns Ulrich Zeilhofer, Gerhard Rammes, Jochen Herms and Mario M. Dorostkar, 28 February 2022, Nature Neuroscience.
DOI: 10.1038/s41593-022-01013-9