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

Tanusree Sen, Nilkantha Sen

Research output: Contribution to journalArticle

10 Scopus citations

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 2 h 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.

Original languageEnglish (US)
Pages (from-to)12-21
Number of pages10
JournalNeurobiology of Disease
Volume96
DOIs
StatePublished - Dec 1 2016

Keywords

  • CREB
  • HDAC
  • Isoflurane
  • Synapse

ASJC Scopus subject areas

  • Neurology

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