Repression of contexual fear memory induced by isoflurane is accompanied by reduction in histone acetylation and rescued by sodium butyrate

Abstract

Isoflurane produces amnesia in mice during contextual fear conditioning (CFC) trials. Histone acetylation is a form of chromatin modification involved in the transcriptional regulation underlying memory formation. We investigated whether isoflurane-induced repression of contextual fear memory is related to altered histone acetylation in the hippocampus, and whether it can be rescued by the histone deacetylases inhibitor sodium butyrate (SB). Adult C57BL/6 mice were chronically given intraperitoneal injections of SB or vehicle for 28 days. Immediately before CFC training, the mice were exposed to isoflurane or air for 30 min and CFC testing was performed the next day. Hippocampal histone acetylation was analysed 1 h after CFC training. c-Fos, an immediate early gene (IEG) suggested to participate in learning and memory formation, was also investigated at the same timepoint. Mice exposed to isoflurane showed a reduction in freezing time during the CFC test. These mice also exhibited reduced hippocampal H3K14, H4K5, and H4K12 acetylation 1 h after CFC training, and also decreased c-Fos expression. All of these changes were attenuated in isoflurane-exposed mice that were chronically treated with SB. Isoflurane suppresses histone acetylation and down-regulates c-Fos gene expression in CA1 of the hippocampus after CFC training. These changes are associated with isoflurane-induced amnesia. The HDAC inhibitor SB prevented repressed contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression in response to CFC training.