Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA_A receptor (GABA_A R). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be "fine-tuned" by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative properties and, at relatively high doses, induced a state of general anaesthesia, a profile consistent with their interaction with GABA_A Rs. However, realising the therapeutic potential of either endogenous neurosteroids or synthetic "neuroactive" steroids has proven challenging. Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat postpartum depression has rekindled enthusiasm for exploring their potential as new medicines. Although neurosteroids are selective for GABA_A Rs, they exhibit little or no selectivity across the many GABA_A R subtypes. Nevertheless, a relatively minor population of receptors incorporating the δ-subunit (δ-GABA_A Rs) appears to be an important contributor to their behavioural effects. Here, we consider how neurosteroids acting upon GABA_A Rs influence neuronal signalling, as well as how such effects may acutely and persistently influence behaviour, and explore the case for developing selective PAMs of δ-GABA_A R subtypes for the treatment of psychiatric disorders.