Neuroinflammation and psychiatric disorders: Relevance of C1q, translocator protein (18 kDa) (TSPO), and neurosteroids

There is increasing evidence that neuroinflammatory processes may play a role in the pathophysiology of psychiatric disorders. Recently, the complement protein C1q and the translocator protein (18 kDa) (TSPO) have attracted considerable interest in this context. C1q is a small molecule which is involved into synaptic pruning mechanisms, increases during ageing and may contribute to neurodegenerative disorders. TSPO is a transmembrane channel protein and mediates numerous biological functions such as bioenergetics and steroid synthesis. Meanwhile, there is evidence that both C1q and TSPO may be elevated in psychiatric disorders, e.g. major depression. Moreover, preclinical and first clinical studies suggest that TSPO ligands may exert antidepressant and anxiolytic properties by promoting endogenous neurosteroid synthesis. In addition, certain neurosteroids, e.g. allopregnanolone, are potent positive allosteric modulators of GABA_A receptors and their composition is altered in depression and anxiety disorders. Recently, neurosteroid compounds such as brexanolone or zuranolone have been reported to reduce depressive and anxiety symptoms in postpartum depression and major depressive disorder. In conclusion, compounds enhancing GABAergic neurotransmission such as neurosteroids and TSPO ligands, which also may exert anti-inflammatory properties in concert with immunomodulators such as C1q may open new avenues for the treatment of psychiatric disorders.