Stress and the major stress hormone corticosterone induce profound influences in the brain. Altered histone modification and transcriptional dysfunction have been implicated in stress-related mental disorders. We previously found that repeated stress caused an impairment of prefrontal cortex (PFC)-mediated cognitive functions by increasing the ubiquitination and degradation of AMPA-type glutamate receptors via a mechanism depending on the E3 ubiquitin ligase Nedd4. Here, we demonstrated that in PFC of repeatedly stressed rats, active glucocorticoid receptor had the increased binding to the glucocorticoid response element of histone deacetylase 2 (HDAC2) promoter, resulting in the upregulation of HDAC2. Inhibition or knock-down of HDAC2 blocked the stress-induced impairment of synaptic transmission, AMPAR expression, and recognition memory. Furthermore, we found that, in stressed animals, the HDAC2-dependent downregulation of histone methyltransferase Ehmt2 (G9a) led to the loss of repressive histone methylation at the Nedd4-1 promoter and the transcriptional activation of Nedd4. These results have provided an epigenetic mechanism and a potential treatment strategy for the detrimental effects of chronic stress.
Key points• Acute stress, via glucocorticoid receptors (GRs), enhances glutamatergic signalling in the prefrontal cortex, a region responsible for high-order cognitive functions.• We found that inhibition or knockdown of histone deacetylase 6 (HDAC6) blocked the enhancement of glutamatergic signalling by acute stress.• Inhibition or knockdown of the GR chaperone protein HSP90 (a substrate of HDAC6) produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling.• These results suggest that HDAC6 is a key molecule regulating the synaptic effects of acute stress in the prefrontal cortex.Abstract The prefrontal cortex (PFC), a region responsible for high-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently it has been shown that acute stress affects PFC functions by potentiating glutamatergic transmission via a mechanism dependent on glucocorticoid receptor (GR) and its downstream target, serum and glucocorticoid-inducible kinase (SGK).To identify the key regulators of stress responses, we examined the role of histone deacetylase 6 (HDAC6), a unique member of the HDAC family that could regulate the GR chaperone protein heat shock protein 90 (HSP90), in the synaptic action of acute stress in PFC. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. These findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.
Účel/cíl: V předchozích studiích bylo popsáno prodloužení intervalu QT u pacientů s cirhózou jater. Naším cílem bylo zkoumat změny na elektrokardiografi ckém (EKG) záznamu a jejich korelaci se závažností onemocnění u pacientů s cirhózou. Metody: Ve studii bylo vyšetřeno celkem 69 pacientů s cirhózou. Prodloužení korigovaného intervalu QT a nízkovoltážní komplexy QRS na EKG záznamu byly zkříženě porovnány s klinickými a biochemickými údaji. Byla zkoumána spojitost EKG nálezů se závažností cirhózy podle Childova-Pughova skóre i skóre z modelu terminálního nemocnění jater (model for end-stage liver diseases, MELD). Výsledky: Prodloužení intervalu QT bylo zjištěno u 63,5 % pacientů a 57,7 % jich splnilo kritéria nízkovoltážních komplexů QRS. U pacientů s prodlouženými intervaly QT sice byly zjištěny vyšší hodnoty Childova-Pughova skóre (9,58 ± 2,5, resp. 8,16 ± 2,29; p = 0,04), avšak při použití MELD byly hodnoty skóre při prodlouženém intervalu QT a nízkovoltážní EKG křivky podobné. Častost výskytu prodlouženého intervalu QT a nízkovoltážních komplexů QRS byla u pacientů v různých třídách Childovy-Pughovy klasifi kace podobná. U pacientů s nízkovoltážní EKG křivkou byla vyšší i srdeční frekvence (89 ± 15 tepů/min, resp. 79 ± 16 tepů/min; p = 0,01). Průměrná voltáž komplexu QRS v prekordiálních svodech byla u pacientů s ascitem nižší (8,5 ± 2,6 mV vs. 11,8 ± 3,4 mV; p = 0,006). Závěr: Změny na elektrokardiogramu jsou u cirhózy bez ohledu na závažnost onemocnění časté. Přítomnost nízkovoltážních komplexů QRS může souviset s antropomorfními změnami a s rozvojem ascitu u této skupiny pacientů.
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