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Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABAA receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABAA receptors either via TSPO ligands or exogenously administered 3α-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3α-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3α-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3α-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3α-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders.

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Data availability

This review does not contain original data with the exception of Figure 4, which was generated in the laboratory of Gerhard Rammes, Experimental Neuropharmacology, Department of Anesthesiology, Technical University Munich.

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Acknowledgements

This work has been supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (DFG), project number 422179811 to RR, CN and JS. Part of this work is part of the thesis of Christian Rupprecht at Faculty of Medicine, Technical University Munich, Germany.

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  1. Department of Psychiatry and Psychotherapy, University Regensburg, Universitätsstrasse 84, 93053, Regensburg, Germany

    Rainer Rupprecht, Marco Kufner, Lisa Marie Brunner, Caroline Nothdurfter, Simon Wein & Jens Schwarzbach

  2. Experimental Neuropharmacology, Department of Anesthesiology, Technical University Munich, Munich, Germany

    Arpit Kumar Pradhan, Xenia Puig, Christian Rupprecht & Gerhard Rammes

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  1. Rainer Rupprecht
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Correspondence to Rainer Rupprecht.

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RR has received consultancy honoraria from SAGE/Biogen and GABA Therapeutics.

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Rupprecht, R., Pradhan, A.K., Kufner, M. et al. Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options. Eur Arch Psychiatry Clin Neurosci 273, 1477–1487 (2023). https://doi.org/10.1007/s00406-022-01532-3

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