Isoflurane-induced inactivation of CREB through histone deacetylase 4 is responsible for cognitive impairment in developing brain

Abstract

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 cfos 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.

The differential effects of isoflurane and sevoflurane on neonatal mice

“…In the present study, we observed reduced levels of PKA-Cα and p-CREB on days 14 and 28 after exposure to isoflurane. This observation is consistent with a previous study that reported the inactivation of CREB by isoflurane, thus resulting in the loss of dendritic outgrowth and the reduced expression of proteins that are essential for memory and cognitive functions in the brains of P7 mice, including BDNF and c-fos 32 . In contrast, in our present study, we found that the levels of PKA-Cα and p-CREB remained unchanged following exposure to sevoflurane.…”

HDAC4 in ischemic stroke: mechanisms and therapeutic potential

“…Growing evidence indicates that HDAC4 may contribute to neurogenesis via regulating the expression and function of multiple molecules. First, HDAC4 regulates the activity and expression of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), respectively, which play a key role in neurogenesis after ischemic stroke [ 18 – 20 , 78 ] (Fig. 1 ).…”

“…However, nuclear shuttling of HDAC4 suppresses the transcriptional activity of CREB by reducing the interaction among acetyltransferase, CBP, and CREB, leading to the reduction of BDNF. [ 18 – 20 ]. In addition, HDAC4 might be another key mediator of the effect of miRNA-9 on neurogenesis in ischemic stroke as HDAC4 is the target of miRNA-9 [ 77 , 79 ].…”

Epigenetic Alterations in Anesthesia-Induced Neurotoxicity in the Developing Brain

“…A decrease in the interaction between CBP and CREB has also been reported in the brains of postnatal mice with isoflurane-induced cognitive impairments, resulting from an increase in nuclear translocation of HDAC4. HDAC4 interacts with CREB in the nucleus, which results in an impairment in transcriptional activation of CREB and a decrease in the expression levels of BDNF and c-Fos ( Sen and Sen, 2016 ). In an isoflurane-exposed maternal-fetal rat model, overexpression of HDAC2 induced the subsequent downregulation of CREB and was associated with spatial learning and memory impairments in the offspring ( Luo et al, 2016 ).…”