Neonatal isoflurane exposure induces neurocognitive impairment and abnormal hippocampal histone acetylation in mice.
BACKGROUND
Neonatal exposure to isoflurane may induce long-term memory impairment in mice. Histone acetylation is an important form of chromatin modification that regulates the transcription of genes required for memory formation. This study investigated whether neonatal isoflurane exposure-induced neurocognitive impairment is related to dysregulated histone acetylation in the hippocampus and whether it can be attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A (TSA).


METHODS
C57BL/6 mice were exposed to 0.75% isoflurane three times (each for 4 h) at postnatal days 7, 8, and 9. Contextual fear conditioning (CFC) was tested at 3 months after anesthesia administration. TSA was intraperitoneally injected 2 h before CFC training. Hippocampal histone acetylation levels were analyzed following CFC training. Levels of the neuronal activation and synaptic plasticity marker c-Fos were investigated at the same time point.


RESULTS
Mice that were neonatally exposed to isoflurane showed significant memory impairment on CFC testing. These mice also exhibited dysregulated hippocampal H4K12 acetylation and decreased c-Fos expression following CFC training. TSA attenuated isoflurane-induced memory impairment and simultaneously increased histone acetylation and c-Fos levels in the hippocampal cornu ammonis (CA)1 area 1 h after CFC training.


CONCLUSIONS
Memory impairment induced by repeated neonatal exposure to isoflurane is associated with dysregulated histone H4K12 acetylation in the hippocampus, which probably affects downstream c-Fos gene expression following CFC training. The HDAC inhibitor TSA successfully rescued impaired contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression.
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Tao
T
Zhong
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Qulian
Q
Guo
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Wangyuan
W
Zou
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Xiaoyan
X
Zhu
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Zongbin
Z
Song
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Bei
B
Sun
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Xin
X
He
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, PR China.
Yong
Y
Yang
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D006657:Histones; D007530:Isoflurane