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Inhibition of BET proteins during adolescence affects prefrontal cortex development: relevance to schizophrenia

ABSTRACT: Background: The present study investigated a role of proteins from BET family (epigenetic readers) in schizophrenia-like abnormalities in MAM-E17 model of schizophrenia. Methods: An inhibitor of BET proteins, JQ1, was given during adolescence in postnatal days (P) 23-P30, and behavioral response (sensorimotor gating, recognition memory) and prefrontal cortex (mPFC) function (long-term potentiation (LTP), molecular and proteomic studies) were performed in adult males and females. Results: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected control, but MAM-treated groups in both sexes. Electrophysiological study showed an LTP impairment only in male MAM-treated animals, and JQ1 did not have any effect on LTP in the mPFC. In contrast, MAM did not affect immediate early gene expression (markers of neuronal and synaptic activity), but JQ1 altered them in both sexes. Proteomic study revealed alterations in MAM-treated groups only in males, while JQ1 affected both sexes. Conclusions: Prenatal MAM administration induced schizophrenia-like abnormalities only in males. In contrast, adolescent JQ1 treatment affected both sexes and induced behavioral changes in control groups, altered a markers of neuronal and synaptic activity and proteomic landscape in the mPFC of both groups (VEH- and MAM-treated). Thus, adolescent inhibition of BET family might change neuroplasticity in the mPFC.

INSTRUMENT(S): ultraflex

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Przemyslaw Mielczarek

LAB HEAD: Marzena Mackowiak

PROVIDER: PXD027050 | Pride | 2021-09-07

REPOSITORIES: Pride

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Inhibition of BET Proteins during Adolescence Affects Prefrontal Cortical Development: Relevance to Schizophrenia.

Bilecki Wiktor W Wawrzczak-Bargieła Agnieszka A Majcher-Maślanka Iwona I Chmelova Magdalena M Maćkowiak Marzena M

International journal of molecular sciences 20210813 16

<h4>Background</h4>The present study investigated the role of proteins from the bromodomain and extra-terminal (BET) family in schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) administration (MAM-E17).<h4>Methods</h4>An inhibitor of BET proteins, JQ1, was administered during adolescence on postnatal days (P) 23-P29, and behavioural responses (sensorimotor gating, recognition memory) and prefrontal cortical (mPFC) functi ...[more]

PMID: 34445411

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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-Î± inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-Î±-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-Î± (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-Î± vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.

Dataset Information

Inhibition of BET proteins during adolescence affects prefrontal cortex development: relevance to schizophrenia

Publications

Inhibition of BET Proteins during Adolescence Affects Prefrontal Cortical Development: Relevance to Schizophrenia.

Similar Datasets

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