Hippocampal 7-Hydroxylated Neurosteroids Are Raised by Training and Bolster Remote Spatial Memory with Increase of the Spine Densities

Neuroactive steroids, termed neurosteroids, are synthesized locally in the brain and influence biological functions including cognition and behavior. These neurosteroids are synthesized from cholesterol by a series of cytochrome P450 enzymes, among which a member of P450 hydroxylase, cytochrome P450-7b1 (CYP7B1), catalyzes the formation of 7 alpha-hydroxylated neurosteroids, 7 alpha-hydroxypregnenolone (7 alpha-OH-Preg) and 7 alpha-hydroxydehydroepiandrosterone (7 alpha-OHDHEA). Here we demonstrated the occurrence of these neurosteroids in the mouse hippocampus after spatial-learning tasks. Cyp7b1 deficiency impaired remote spatial memory with recent memory mostly unaffected. The hippocampal dendritic spine densities were reduced in Cyp7b1-deficient mice, and they were no more increased by the training. Furthermore, chronic intracerebroventricular administration of a mixture of 7 alpha-OH-Preg and 7 alpha-OH-DHEA rescued the deteriorated remote memory performance in Cyp7b1-deficient mice. It is concluded that the 7 alpha-hydroxylated neurosteroids are required for long-term maintenance of spatial memory, and we suggest that these neurosteroids may induce synaptic remodeling to maintain the hippocampal function.