Pregnenolone sulfate acts through a G-protein-coupled sigma1-like receptor to enhance short term facilitation in adult hippocampal neurons.

Neurosteroids have been linked to cognitive performance, and their levels are altered in neuropsychiatric diseases. These neuromodulators are produced in the brain where they have important effects on synaptic transmission at postsynaptic gamma-amino-butyric acid receptors and N-methyl-D-aspartate receptors and at presynaptic sites. We previously found, in cultured neonatal hippocampal neurons, that the neurosteroid, pregnenolone sulfate, acts presynaptically through a sigma1-like receptor to modulate basal glutamate release. The present study was designed to test whether pregnenolone sulfate acts through a similar presynaptic receptor in adult hippocampal neurons. The sigma1-receptor agonist, 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate, enhanced paired-pulse facilitation (PPF) by a similar extent to that which we had previously reported for pregnenolone sulfate. The sigma1-receptor antagonists, 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine and 1[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine, blocked the pregnenolone sulfate enhancement of PPF as did pretreatment of slices in pertussis toxin. We conclude that pregnenolone sulfate acts through a Gi/o-coupled sigma1-like receptor to enhance short-term presynaptic facilitation onto adult hippocampal CA1 neurons.