Physiological roles for the neurosteroid allopregnanolone in the modulation of brain function during pregnancy and...

Allopregnanolone is a well-established allosteric modulator of the GABAA receptor but its physiological roles within the nervous system remain unclear. Derived principally from circulating progesterone, allopregnanolone achieves its highest concentrations within the nervous system during late pregnancy and recent studies have now begun to elucidate its roles at this time in the rat. At the molecular level it is clear that the regulation of GABAA receptor subunit gene expression by progesterone and its derivatives occurs in a subunit- and a neuron-specific manner and that both progesterone and allopregnanolone are involved. At the cellular level, the increasing concentrations of allopregnanolone with advancing pregnancy can be shown to have important physiological actions in repressing the electrical activity of specific neuronal phenotypes such as the magnocellular oxytocin neurons. The marked fall in progesterone and allopregnanolone concentrations prior to parturition equally appears to have a substantial impact upon GABAA receptor signaling in the hippocampus, frontal cortex and oxytocin neurons. Together, studies at a basic level suggest that the rise and fall in allopregnanolone concentrations during pregnancy are likely to exert a powerful regulatory influence upon neurotransmission in a variety of brain networks. The temporal correlation between these events and the observed cognitive, psychiatric and physiological changes associated with pregnancy and the peri-partum period in humans is striking and warrants close attention.