ABSTRACT
Conventionally, steroids operate via transcription, but a subclass of brain-active steroids, dubbed neurosteroids, may govern cognitive processes via membrane-associated receptors. De novo synthesis of neurosteroids within the brain has been discussed; we suggest that these may derive primarily from the circulation. In contrast, the brain is largely self-sufficient in cholesterol. Synthesis and metabolism of cholesterol and its oxysterol derivatives appears to be crucial to brain development and function, emphasized by drugs (anti-convulsants, neuroleptics) and mutations (Smith-Lemli-Opitz, Niemann-Pick disease type C, cerebrotendinous xanthamatosis) that affect these pathways and have marked brain effects. Receptors for steroids and sterols are discussed, particularly those at cell-surface and intracellular membranes including sites of sterol metabolism and trafficking (including sigma-1, the emopamil binding protein [EBP], and the peripheral benzodiazepine receptor [PBR]). Potential overlaps between sterol and steroid signaling are discussed. In addition to regulating neuronal activity, we suggest that steroids and sterols may regulate proliferative and degenerative processes in the brain including apoptosis induction. Evidence is presented for cross-talk between activity of neurotransmitter receptors at the cell surface (e.g., GABAA) and pathways operating within the cell; local sterol signaling could potentially extend between cells. We also address whether changes in neurosteroid signaling mediated by the adrenal steroid dehydroepiandrosterone (DHEA) could contribute to age-related cognitive impairments.
