The Role of Chromatin Plasticity in Schizophrenia and Anxiety Diseases

Schizophrenia is a severe neuropsychiatric disorder with high phenotypic complexity and multifactorial inheritance. Cognitive dysfunctions have been identified as the core feature of the disease and they are resistant to treatment with available antipsychotics. Impaired working memory and disrupted sensorimotor gating are the cognitive hallmarks of schizophrenia. Both of these cognitive dysfunctions are defined as cognitive endophenotypes that present a biomarker and guidepost for identification of the cause and course of schizophrenia. The etiopathogenesis of schizophrenia is thought to rely on genome and environment (GxE) interactions. Epigenetic enzymes such as histone-deacetylases (HDACs) are key mediators of GxE interactions. HDACs remove acetyl-groups of histone-proteins in response to environment stimuli, thereby changing the chromatin structure resulting into differential gene-expression important for cognition. Deregulated histone-acetylation leads to impairments in learning and memory. Two independent human post-mortem studies have reported elevated HDAC1 levels in the hippocampus and prefrontal cortex of individuals with schizophrenia, with both brain regions being important for the regulation of cognitive endophenotypes of schizophrenia. My results showed, that overexpression of neuronal HDAC1 in the prefrontal cortex of adult mice resulted in schizophrenia-like symptoms such as increased anxiety, depressive-like behavior, impaired fear extinction and cognitive endophenotypes such as impaired working memory performance and deficits in sensorimotor gating function. Inhibition of HDAC1 ameliorated such phenotypes. Moreover, environmental risk factors for schizophrenia such as early life stress induced cognitive endophenotypes of schizophrenia and mediated the up-regulation of prefrontal cortical HDAC1, simulating the situation observed in the post-mortem prefrontal cortex tissue of individuals with schizophrenia. . Interestingly, while manipulating neuronal HDAC1 levels in the prefrontal cortex of mice caused schizophrenia-like phenotypes, affecting neuronal HDAC1 levels in the dorsal hippocampus had no impact on such behaviors. Instead under physiological conditions, HDAC1 in the dorsal hippocampus regulates the extinction of fear memories in mice by transcriptional repression of Immediate Early Genes (IEG´s). In conclusion, these data indicate a brain-region specific function of HDAC1 in cognition and emotional behavior and provide important knowledge on the role of HDAC1 in the adult brain

Histone-acetylation: a link between Alzheimer's disease and post-traumatic stress disorder?

The orchestration of gene-expression programs is essential for cellular homeostasis. Epigenetic processes provide to the cell a key mechanism that allows the regulation of gene-expression networks in response to environmental stimuli. Recently epigenetic mechanisms such as histone-modifications have been implicated with cognitive function and altered epigenome plasticity has been linked to the pathogenesis of neurodegenerative and neuropsychiatric diseases. Thus, key regulators of epigenetic gene-expression have emerged as novel drug targets for brain diseases. Numerous recent review articles discuss in detail the current findings of epigenetic processes in brain diseases. The aim of this article is not to give yet another comprehensive overview of the field but to specifically address the question why the same epigenetic therapies that target histone-acetylation may be suitable to treat seemingly different diseases such as Alzheimer's disease and post-traumatic stress disorder

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia

HDAC1 links early life stress to schizophrenia-like phenotypes.

Significance Early life stress (ELS) is an important risk factor for schizophrenia. Our study shows that ELS in mice increases the levels of histone-deacetylase (HDAC) 1 in brain and blood. Although altered Hdac1 expression in response to ELS is widespread, increased Hdac1 levels in the prefrontal cortex are responsible for the development of schizophrenia-like phenotypes. In turn, administration of an HDAC inhibitor ameliorates ELS-induced schizophrenia-like phenotypes. We also show that Hdac1 levels are increased in the brains of patients with schizophrenia and in blood from patients who suffered from ELS, suggesting that the analysis of Hdac1 expression in blood could be used for patient stratification and individualized therapy. </jats:p

Histone-Methyltransferase MLL2 (KMT2B) Is Required for Memory Formation in Mice

The consolidation of long-term memories requires differential gene expression. Recent research has suggested that dynamic changes in chromatin structure play a role in regulating the gene expression program linked to memory formation. The contribution of histone methylation, an important regulatory mechanism of chromatin plasticity that is mediated by the counteracting activity of histone-methyltransferases and histone-demethylases, is, however, not well understood. Here we show that mice lacking the histone-methyltransferase myeloid/lymphoid or mixed-lineage leukemia 2 (mll2/kmt2b) gene in adult forebrain excitatory neurons display impaired hippocampus-dependent memory function. Consistent with the role of KMT2B in gene-activation DNA microarray analysis revealed that 152 genes were downregulated in the hippocampal dentate gyrus region of mice lacking kmt2b. Downregulated plasticity genes showed a specific deficit in histone 3 lysine 4 di- and trimethylation, while histone 3 lysine 4 monomethylation was not affected. Our data demonstrates that KMT2B mediates hippocampal histone 3 lysine 4 di- and trimethylation and is a critical player for memory formation

microRNA-34c is a novel target to treat dementias

MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR-34c could be a suitable therapy

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia

DNA methylation changes in plasticity genes accompany the formation and maintenance of memory

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