ELUCIDATION OF THE PHYSIOLOGICAL SIGNIFICANCE AND MOLECULAR RESPONSES OF 7Α-HYDROXYLATED NEUROSTEROIDS IN REMOTE SPATIAL MEMORY

Neurosteroids are a group of steroid hormones synthesized from cholesterol in the brain. 7α-hydroxy-neurosteroids (7α-hydroxypregnenolone [7α-OH-Preg] and 7α-hydroxydehydroepiandrosterone [7α-OH-DHEA]) are synthesized by a member of the P450 hydroxylase family, CYP7B1. CYP7B1 was expressed widely in the mouse brain with high levels in the hippocampus. We identified the presence of 7α-OH-Preg and 7α-OH-DHEA in the mouse hippocampus after the Morris’s water maze task using LC-MS/MS. Cyp7b1 deficiency impaired remote spatial memory, whereas recent memory was mostly unaffected. Hippocampal dendritic spine densities were reduced in Cyp7b1-deficient mice. Spine densities were no longer increased by training in Cyp7b1-deficient mice, although these were significantly increased by training in wild-type mice. Furthermore, chronic intracerebroventricular administration of 7α-OH-Preg and 7α-OH-DHEA improved the spine density and remote spatial memory performance in Cyp7b1-deficient mice. Interestingly, co-infusion of these neurosteroids was more effective than infusion of each steroid individually, despite the concentrations being the same. These results indicate that CYP7B1 is crucial for the long-term maintenance of spatial memory, via the actions of 7α-OH-Preg and 7α-OH-DHEA, and that these steroids function in a cooperative manner (iScience 2020). It is relevant to identify their individual targets for understanding how they regulate remote spatial memory. RNAseq results from the administration of the neurosteroids in the Cyp7b1 KO mouse showed that a group of molecules involved in neurological disorders are altered. We are elucidating the targets and molecular mechanism of spine remodeling and spatial memory maintenance by neurosteroids using transcriptomic analysis.