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Antipsychotic-induced Hdac2 transcription via NF-?B leads to synaptic and cognitive side effects.

ABSTRACT: Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-?B in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-?B repressor I?B?. This upregulation of NF-?B activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-?B signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

SUBMITTER: Ibi D

PROVIDER: S-EPMC5675106 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.

Ibi Daisuke D de la Fuente Revenga Mario M Kezunovic Nebojsa N Muguruza Carolina C Saunders Justin M JM Gaitonde Supriya A SA Moreno José L JL Ijaz Maryum K MK Santosh Vishaka V Kozlenkov Alexey A Holloway Terrell T Seto Jeremy J García-Bea Aintzane A Kurita Mitsumasa M Mosley Grace E GE Jiang Yan Y Christoffel Daniel J DJ Callado Luis F LF Russo Scott J SJ Dracheva Stella S López-Giménez Juan F JF Ge Yongchao Y Escalante Carlos R CR Meana J Javier JJ Akbarian Schahram S Huntley George W GW González-Maeso Javier J

Nature neuroscience 20170807 9

Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cort ...[more]

PMID: 28783139

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Project description: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.

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Antipsychotic-induced Hdac2 transcription via NF-?B leads to synaptic and cognitive side effects.

Publications

Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.

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