Increased membrane cholesterol reduces the potentiation of GABA A currents by neurosteroids in dissociated hippocampal neurones

The effects of increased membrane cholesterol on the potentiation of GABA A currents by pregnanolone (5 β-pregnan-3 α-ol-20-one), allopregnanolone (5 α-pregnan-3 α-ol-20-one), alphaxalone (5 α-pregnan-3 α-ol-11,20-dione) and propofol were investigated in acutely dissociated rat hippocampal neurones using the whole-cell patch clamp technique. Cholesterol enrichment of the neurones, isolated from 10 to 16-day-old Wistar rat brains, was achieved by incubation with cholesterol+phosphatidylcholine liposomes. Cholesterol enrichment (25.8±3.4%) reduced the potentiation of GABA A currents by pregnanolone (0.3 and 1 μM), allopregnanolone (1 μM) and alphaxalone (1 μM) but the potentiation of GABA A currents by propofol (5 μM) was not affected. Acute application of cholesterol (1 μM) did not significantly change the potentiation of GABA A currents by pregnanolone (1 μM). These results suggest that cholesterol within the neuronal membrane may compete with neurosteroids for their sites of action on the GABA A receptor or modulate the potentiating effect of the neurosteroids in some other ways.