Neurosteroids in the Hippocampus: Neuronal Plasticity and Memory

The hippocampus, which is critically involved in learning and memory processes, is known to be a target for the neuromodulatory actions of steroid hormones produced by the adrenal glands and gonads. Much of the work of B.S. McEwen and collaborators has focused on the role of glucocorticosteroids and estrogen in modulating hippocampal plasticity and functions. In addition to hormones derived from the endocrine glands, cells in the hippocampus may be exposed to locally synthesized neurosteroids, including pregnenolone, dehydroepiandrosterone and their sulfated esters as well as progesterone and its reduced metabolites. In contrast to hormones derived from the circulation, neurosteroids have paracrine and/or autocrine activities. In the hippocampus, they have been shown to have trophic effects on neurons and glial cells and to modulate the activity of a variety of neurotransmitter receptors and ion channels, including type A gamma-aminobutyric acid, N-methyl-D-aspartate and sigma receptors and N- and L-type Ca2+ channels. There is accumulating evidence that some neurosteroids, in particular pregnenolone sulfate, have strong influences on learning and memory processes, most likely by regulating neurotransmission in the hippocampus. However, the hippocampus is not the only target for the mnesic effects of neurosteroids. Associated brain regions, the basal nuclei of the forebrain and the amygdaloid complex, are also involved. Some neurosteroids may thus be beneficial for treating age- or disease-related cognitive impairments.