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Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?

Abstract

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABAA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABAA receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.

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Fig. 1: Schematic presentation of various cellular functions of TSPO.
Fig. 2: Diazepam may lead to synapse loss by increased microglial synaptic pruning via TSPO.
Fig. 3: Neuroimaging-derived parameters using machine learning (ML) and artificial intelligence (AI) models may predict the speed and efficiency of a therapeutic intervention with TSPO ligands.

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Acknowledgements

This work has been supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (DFG), project number 422179811 to RR and JS, 421887978 to NLA, 422182557 to CHW, 422174053 to MS, 422181340 to MD and JH, 422183249 to IDN, the DFG graduate school GRK2174 to IN and RR, and EXC 2145 SyNergy – ID 390857198 to JH.

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RR drafted and revised the whole manuscript, CW contributed to the chapter on mitochondria, MS to the neurosteroid part, MD and JH contributed findings on neuroplasticity, IDN to the chapter on animal models, and JS and NA to the clinical neuroimaging part. All authors carefully read and revised the manuscript.

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Correspondence to Rainer Rupprecht.

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RR has received consultancy honoraria from SAGE and GABA Therapeutics.

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Rupprecht, R., Wetzel, C.H., Dorostkar, M. et al. Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?. Mol Psychiatry 27, 2918–2926 (2022). https://doi.org/10.1038/s41380-022-01561-3

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