Sen Tanusree, Sen Nilkantha
University of Georgia, Department of Veterinary, USA.
Augusta University, Department of Neuroscience and Regenerative Medicine, 1120 15th Street, CA 2018, Augusta, GA 30907, USA.
Neurobiol Dis. 2016 Dec;96:12-21. doi: 10.1016/j.nbd.2016.08.005. Epub 2016 Aug 17.
Anesthetics including isoflurane are known to induce neuronal dysfunction in the developing brain, however, the underlying mechanism is mostly unknown. The transcriptional activation of CREB (cyclic AMP response element binding protein) and the alterations in acetylation of histones modulated by several histone deacetylases such as HDAC4 (histone deacetylase 4) are known to contribute to synaptic plasticity in the brain. Here we have shown that administration of isoflurane (1.4%) for 2h leads to transcriptional inactivation of CREB which results in loss of dendritic outgrowth and decreased expression level of proteins essential for memory and cognitive functions, such as BDNF, and c-fos in the developing brain of mice at postnatal day 7 (PND7). To elucidate the molecular mechanism, we found that exposure to isoflurane leads to an increase in nuclear translocation of HDAC4, which interacts with CREB in the nucleus. This event, in turn, results in a decrease in interaction between an acetyltransferase, CBP, and CREB that ultimately leads to transcriptional inactivation of CREB. As a result, the expression level of BDNF, and c-fos were significantly down-regulated after administration of isoflurane in PND7 brain. Depletion of HDAC4 in PND7 brain rescues the transcriptional activation of CREB along with augmentation in the level of the expression level of BDNF and c-fos. Moreover, administration of lentiviral particles of HDAC4 RNAi in primary neurons rescues neurite outgrowth following isoflurane treatment. Taken together, our study suggests that HDAC4-induced transcriptional inactivation of CREB is responsible for isoflurane-induced cognitive dysfunction in the brain.
包括异氟烷在内的麻醉剂已知会在发育中的大脑中诱发神经元功能障碍，然而，其潜在机制大多未知。已知CREB（环磷腺苷反应元件结合蛋白）的转录激活以及由几种组蛋白去乙酰化酶（如HDAC4，组蛋白去乙酰化酶4）调节的组蛋白乙酰化改变有助于大脑中的突触可塑性。在此我们表明，在出生后第7天（PND7）给小鼠发育中的大脑施用2小时1.4%的异氟烷会导致CREB的转录失活，这会导致树突生长丧失以及对记忆和认知功能至关重要的蛋白质（如脑源性神经营养因子（BDNF）和c-fos）的表达水平降低。为了阐明分子机制，我们发现暴露于异氟烷会导致HDAC4的核转位增加，HDAC4在细胞核中与CREB相互作用。反过来，这一事件会导致乙酰转移酶CBP与CREB之间的相互作用减少，最终导致CREB的转录失活。结果，在PND7大脑中施用异氟烷后，BDNF和c-fos的表达水平显著下调。在PND7大脑中耗尽HDAC4可挽救CREB的转录激活，同时BDNF和c-fos的表达水平也会升高。此外，在原代神经元中施用HDAC4 RNAi的慢病毒颗粒可挽救异氟烷处理后的神经突生长。综上所述，我们的研究表明，HDAC4诱导的CREB转录失活是异氟烷诱导的大脑认知功能障碍的原因。
