A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission

The endogenous neurosteroid pregnenolone sulfate (PS) is known to enhance memory and cognitive function at nanomolar concentrations. However, the effect of these low concentrations on synaptic transmission has not been previously studied. The effects of PS on GABA(A) receptor-mediated inhibitory postsynaptic currents were studied in cultured hippocampal pyramidal neurons. Concentrations of PS similar to those endogenous in the hippocampus (10-30 nM) reduced the frequency of both action potential-dependent (spontaneous inhibitory postsynaptic current) and -independent (miniature inhibitory postsynaptic current; mIPSC) inhibitory postsynaptic currents. This effect of PS was mimicked by the selective sigma(1) receptor agonist [2S-(2alpha,6alpha,11R]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride [(+)-SKF 10047] and blocked the specific sigma(1) receptor antagonists 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) and haloperidol and by pertussis toxin. The GABA(B) antagonist baclofen and the metabotropic glutamate receptor antagonist (R,S)-a-cyclopropyl-4-phosphonophenylglycine had no effect on the PS-mediated inhibition of mIPSC frequency. The postsynaptic effects of PS occurred at micromolar concentrations but not at nanomolar concentrations. A comparison of the pre- and postsynaptic effects of PS demonstrated that it was 100-fold more potent in inhibiting presynaptic GABAergic synaptic mechanisms than GABA A receptors. These studies demonstrate that concentrations of PS, similar to those endogenous in the hippocampus, inhibit GABAergic synaptic transmission by a presynaptic effect. PS causes specific activation of G protein-coupled sigma(1) receptors, resulting in modulation of both action potential-dependent and -independent IPSCs. These findings improve our understanding of the physiological function of PS.