Histone Modification ofNedd4Ubiquitin Ligase Controls the Loss of AMPA Receptors and Cognitive Impairment Induced by Repeated Stress

Abstract

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.

Blast waves from detonated military explosive reduce GluR1 and synaptophysin levels in hippocampal slice cultures

“…It is of interest that the military blast-induced synaptic decline corresponds with increases in HDAC2, a protein whose upregulation has been linked to GluR1 degradation (Wei et al, 2016). As shown in Fig.…”

“…When exposed to consecutive RDX detonations, GluR1 levels were further reduced by as much as 72% after three blasts. A correlational analysis indicates that such synaptic decline may be mediated in part by HDAC2, a histone deacetylase whose upregulation has been associated with stress-induced GluR1 degradation, loss of glutamatergic transmission, and disrupted recognition memory (Wei et al, 2016). The link to HDAC2 also implicates alterations to AMPA receptor sorting pathways in the blast-induced synaptic decline, since HDAC2-related pathways have been found to play a role in regulating AMPA receptor trafficking (Schwarz et al, 2010; Hou et al, 2011) and ubiquitin/proteasome-mediated degradation of GluR1 which can lead to the deficit of certain cognitive processes (Yuen et al, 2012).…”

Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism

“…No sample was excluded from the analysis. The sample size was based on power analyses and was similar to those reported in previous work [18,30,31]. The variance between groups being statistically compared was similar.…”

“…Biochemical measurement of total, surface, nuclear, and synaptic proteins Nuclear extracts from mouse brains were prepared as we previously described [30]. Briefly, ten frontal cortical punches (diameter: 2 mm) from fresh mouse slices (300 μm) per animal were collected, and then homogenized with 500 μl homogenization buffer (20 mM Tris-HCl, pH 7.4, 10 mM NaCl, 3 mM MgCl 2 , 0.5% NP-40, 1 mM PMSF, with cocktail protease inhibitor).…”

Efeitos comportamentais e neuroplásticos da combinação de escitalopram e canabinóides

“…Por outro lado, cronicamente, haveria uma dessensibilização desses autorreceptores e, dessa forma, o aumento da disponibilidade de 5-HT seria muito mais marcante. FASS et al, 2014;MATTSON et al, 2018;TARDITO et al, 2006 As manifestações neuroplásticas maladaptativas descritas em condições de estresse crônico em modelos animais incluem atrofia da arborização dendrítica e redução do número de espinhos dendríticos de neurônios piramidais da região CA3 e de neurônios piramidais das camadas II e III do córtex pré-frontal medial (CHEN et al, 2008;COOK;WELLMAN, 2004;HAINS et al, 2009;MAGARIÑOS et al, 1996;MAGARIÑOS;MCEWEN, 1995;RADLEY et al, 2006;WATANABE;GOULD;MCEWEN, 1992), prejuízo na indução de potenciação de longo prazo (long-term potentiation, LTP) na via perforante, nos colaterais de Schaffer e na via hipocampocórtex pré-frontal (CERQUEIRA et al, 2007;FOY et al, 1987;KIM;FOY;THOMPSON, 1996;MCEWEN, 1999;DRYVER, 1994;SERVATIUS, 1995), facilitação do fenômeno de depressão de longo prazo (long-term depression, LTD) nos colaterais de Schaffer (KIM; FOY; THOMPSON, 1996), redução nos níveis de fatores neurotróficos como BDNF (HASHIKAWA et al, 2015;THAKARE et al, 2017;VAN BOXELAERE et al, 2017;ZU et al, 2017), diminuição na expressão de proteínas de estabilidade sináptica, como PSD95 (ZHAO et al, 2017), alterações na maquinaria de liberação de neurotransmissores (MÜLLER et al, 2011;THOME et al, 2001;ZHAO et al, 2017), alteração na expressão e função de receptores, incluindo receptores glutamatérgicos AMPA e NMDA (WEI et al, 2016;…”