HDAC2 hyperexpression alters hippocampal neuronal transcription and microglial activity in neuroinflammation-induced cognitive dysfunction

Abstract

BackgroundInflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown.MethodsThree-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus.ResultsLPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII+ neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus ShHdac2, which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits.ConclusionsReversing HDAC2 in hippocampal CaMKII+ neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

The Expression of Interleukin-1β Is Regulated by DNA Methylation in Microglia of Hippocampus to Participate Postoperative Cognitive Dysfunction in Aged Mice

“…Consistent with this was that the general anesthetic may impair developing neurons and induce young adult male C57BL/6 mice cognitive dysfunction in a dose-and time-dependent manner [60,61]. We also found that LPS-impaired object recognition and fear memory were not aggravated by iso urane in adult mice [29]. Simultaneously Silbert BS et al also found no signi cant difference in the rates of POCD when comparing general anaesthesia (contained iso urane) with spinal anaesthesia, suggesting that the surgical or procedural process itself may contribute to the development of POCD [62].…”

“…Mice were perfused transcardially via the left ventricle with 0.9% saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). The brain tissues were harvested and post xed in 4% paraformaldehyde overnight and dehydrated in 30% sucrose as we reported before [29]. Sections (35 µm thick) were sliced with a freezing microtome (Leica CM1950, Germany).…”

“…the above cells were divided into four groups: LPS (-) + Lenti-DNMT3a group, LPS (-) + Lenti-Empty group, LPS (+) + Lenti-DNMT3a group, LPS (+) + Lenti-Empty group. The treatment included LPS (1 µg / ml) or left untreated for 4 h [29].…”

Epigenetic Modulation of Microglia Function and Phenotypes in Neurodegenerative Diseases

“…A subsequent study has revealed that microglia activation mediates overexpression of HDAC2, reduces levels of histone acetylation, and suppresses transcription and expression of BDNF and c-fos, leading to memory impairment. Then, injection of the adenoassociated virus (ShHDAC2) in the dorsal hippocampus attenuates microglia activation and effectively reversed these pathological processes [ 127 ]. Zhu et al [ 128 ] have shown that overexpression of HDAC3 promotes A β levels and microglia activation, as well as reduces the density of dendritic spine in the hippocampus of APP/PS1 mice, while lentivirus-mediated inhibition of HDAC3 attenuates microglia activation and ameliorates cognition, as well as improves AD-related neuropathogenesis.…”

BNSTAVGABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice

“…Maternal separation (MS) is commonly adopted as an ELS model to investigate the underlying mechanisms of functional gastrointestinal and psychiatric disorders ( O'Mahony et al, 2009 ). ELS is known to affect the development of synaptic plasticity and neural circuits ( Sun et al, 2019 ). Our previous studies identified that corticotrophin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) and hypothalamic-pituitary-adrenal (HPA) axis were involved in the development of MS-induced visceral hypersensitivity ( Zhang et al, 2016 ; Tang et al, 2017 ).…”