| Autor: |
Shu HJ; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Ziolkowski LH; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Salvatore SV; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Benz AM; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Wozniak DF; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.; Taylor Family Institute for Innovative Psychiatry Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Yuede CM; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Paul SM; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.; Taylor Family Institute for Innovative Psychiatry Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Zorumski CF; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.; Taylor Family Institute for Innovative Psychiatry Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA., Mennerick S; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.; Taylor Family Institute for Innovative Psychiatry Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA. |
| Abstrakt: |
Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior. |
