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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
T
T
Zhong
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
Q J
QJ
Qing
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
Y
Y
Yang
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
W Y
WY
Zou
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
Z
Z
Ye
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China.
J Q
JQ
Yan
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, PR China guoqulian@gmail.com.
Q L
QL
Guo
D000107:Acetylation; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005239:Fear / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis
D018685:Anesthetics, Inhalation; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D020148:Butyric Acid; D007530:Isoflurane
amnesia; anaesthetics volatile, isoflurane; epigenetics, acetylation; hippocampus; mice; proto-oncogene proteins c-Fos; sodium butyrate