Epigenetic regulation of general anesthesia-induced neonatal neurodegeneration

General anesthesia-induced neurocognitive dysfunction in the developing brain has been well documented [1], yet the underlying mechanisms remain incompletely understood. Epigenetic mechanism is thought to be a key regulator of gene-environment interactions and have been implicated in the etiology of various brain disorders. Histone acetylation is one of the most studied epigenetic modifications and controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs), which add or remove acetyl groups from protein substrates, respectively. Although its regulation is extraordinarily complex and dynamic, it is generally considered that an increase in histone acetylation induces chromatin structure from a tightly packed configuration to a loose one and subsequently results in transcriptional activation. By contrast, a decrease in histone acetylation mediated by HDACs condenses chromatin structure and leads to transcriptional silencing. There is accumulating evidence indicating that aberrant histone acetylation plays a critical role in the cognitive impairment that is associated with psychiatric and neurodegenerative disorders. Presently unclear, however, is how altered histone acetylation participates in the pathogenesis of general anesthesia-induced neonatal neurocognitive impairments. Our recently published study in Neurobiology of Disease reported that neonatal exposure to sevoflurane induces neurobehavioral impairments with concurrent long-lasting down-regulation of hippocampal histone acetylation. To further address the causal role of histone acetylation, we normalized histone acetylation by using class I HDACs inhibitor sodium butyrate (NaB) and found the improved neurobehavioral abnormities [2], indicating that histone acetylation plays a key role in sevoflurane exposure induced-neurobehavioral impairments. Of note, our study further showed that normalization of hippocampal histone acetylation after NaB treatment could rescue the decreased levels of synapse-related proteins, including BDNF, synapsin1, PSD95, pCREB/ CREB, CBP, and restore the loss of dendritic spines in the CA1 pyramidal neurons. Although our study did not exclude that additional mechanisms are involved, our results suggested a potential mechanism by which down-regulated hippocampal histone acetylation can participate in general anesthesia-induced cognitive impairments in neonates. The highly expressed class I HDACs (including HDAC1, 2, 3 and 8) in the central nervous system suggest broad roles of these enzymes in controlling histone acetylation and transcription. Taking into account that NaB belongs to a pan-HDACs inhibitor, the question of contribution of individual HDACs toward general anesthesia-induced neonatal neurocognitive abnormalities arises. Using a combination of pharmacological and genetic approaches, it has been suggested that HDAC2 but not HDAC1 is a specific negative regulator of synaptic plasticity and memory formation [3]. Unlike HDAC1 and …