scholarly journals DNA Methylation-Mediated Modulation of Endocytosis as Potential Mechanism for Synaptic Function Regulation in Murine Inhibitory Cortical Interneurons

2020 ◽  
Vol 30 (7) ◽  
pp. 3921-3937 ◽  
Author(s):  
Daniel Pensold ◽  
Julia Reichard ◽  
Karen M J Van Loo ◽  
Natalja Ciganok ◽  
Anne Hahn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Information Processing ◽  
Transcriptional Control ◽  
Synaptic Function ◽  
Adult Brain ◽  
Potential Implication ◽  
Gabaergic Transmission ◽  
Cortical Interneurons ◽  
Subcellular Processes ◽  
Cortical Information Processing

Abstract The balance of excitation and inhibition is essential for cortical information processing, relying on the tight orchestration of the underlying subcellular processes. Dynamic transcriptional control by DNA methylation, catalyzed by DNA methyltransferases (DNMTs), and DNA demethylation, achieved by ten–eleven translocation (TET)-dependent mechanisms, is proposed to regulate synaptic function in the adult brain with implications for learning and memory. However, focus so far is laid on excitatory neurons. Given the crucial role of inhibitory cortical interneurons in cortical information processing and in disease, deciphering the cellular and molecular mechanisms of GABAergic transmission is fundamental. The emerging relevance of DNMT and TET-mediated functions for synaptic regulation irrevocably raises the question for the targeted subcellular processes and mechanisms. In this study, we analyzed the role dynamic DNA methylation has in regulating cortical interneuron function. We found that DNMT1 and TET1/TET3 contrarily modulate clathrin-mediated endocytosis. Moreover, we provide evidence that DNMT1 influences synaptic vesicle replenishment and GABAergic transmission, presumably through the DNA methylation-dependent transcriptional control over endocytosis-related genes. The relevance of our findings is supported by human brain sample analysis, pointing to a potential implication of DNA methylation-dependent endocytosis regulation in the pathophysiology of temporal lobe epilepsy, a disease characterized by disturbed synaptic transmission.

scholarly journals Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Darina Czamara ◽  
Elleke Tissink ◽  
Johanna Tuhkanen ◽  
Jade Martins ◽  
Yvonne Awaloff ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Social Services ◽  
Disease Risk ◽  
Childhood Adversity ◽  
Total Sample ◽  
Synaptic Function ◽  
Combined Effects ◽  
Self Reports ◽  
Main Effects ◽  
The Impact

AbstractLasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

scholarly journals Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease

2019 ◽  
Vol 20 (14) ◽  
pp. 3407 ◽  
Author(s):  
Paola Imbriani ◽  
Annalisa Tassone ◽  
Maria Meringolo ◽  
Giulia Ponterio ◽  
Graziella Madeo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Caspase 3 ◽  
Cysteine Proteases ◽  
Synaptic Function ◽  
Adult Brain ◽  
Striatal Slices

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

scholarly journals 25. Cortical Information Processing in Patients With Schizophrenia is Modulated by Tolcapone: Role of COMT val158met Genotype

2017 ◽  
Vol 43 (suppl_1) ◽  
pp. S17-S17
Author(s):  
Jose Apud ◽  
Yunxia Tong ◽  
Roberta Rasetti ◽  
Teresa Vargas ◽  
Joseph Callicott ◽  
...  
Keyword(s):  
Information Processing ◽  
Comt Val158met ◽  
Cortical Information Processing

scholarly journals Global Modulation in DNA Epigenetics during Pro-Inflammatory Macrophage Activation

2019 ◽  
Author(s):  
Nikhil Jain ◽  
Tamar Shahal ◽  
Tslil Gabrieli ◽  
Noa Gilat ◽  
Dmitry Torchinsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Single Molecule ◽  
Transcriptional Control ◽  
Excision Repair ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Inflammatory Activation ◽  
Methylation Patterns

AbstractDNA methylation patterns create distinct gene expression profiles. These patterns are maintained after cell division, thus enabling the differentiation and maintenance of multiple cell types from the same genome sequence. The advantage of this mechanism for transcriptional control is that chemical-encoding allows to rapidly establish new epigenetic patterns “on-demand” through enzymatic methylation and de-methylation of DNA. Here we show that this feature is associated with the fast response of macrophages during their pro-inflammatory activation. By using a combination of mass spectroscopy and single-molecule imaging to quantify global epigenetic changes in the genomes of primary macrophages, we followed three distinct DNA marks (methylated, hydroxymethylated and unmethylated), involved in establishing new DNA methylation patterns during pro-inflammatory activation. The observed epigenetic modulation together with gene expression data generated for the involved enzymatic machinery, may suggest that de-methylation upon LPS-activation starts with oxidation of methylated CpGs, followed by excision-repair of these oxidized bases and their replacement with unmodified cytosine.

scholarly journals Transcriptional control and exploitation of an immune-responsive family of plant retrotransposons

2017 ◽  
Author(s):  
Jérôme Zervudacki ◽  
Agnès Yu ◽  
Delase Amesefe ◽  
Jingyu Wang ◽  
Jan Drouaud ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Plant Defense ◽  
Transcriptional Control ◽  
Plant Immunity ◽  
Disease Resistance Gene ◽  
Loss Of Function ◽  
Long Terminal Repeats ◽  
Protein Coding ◽  
Regulatory Modules ◽  
Microrna Genes

ABSTRACTMobilization of transposable elements (TEs) in plants has been recognized as a driving force of evolution and adaptation, in particular by providing genes with regulatory modules that impact their transcription. In this study, we employed anATCOPIA93Long terminal repeats (LTR) promoter-GUSfusion to show that this retrotransposon behaves like an immune-responsive gene during plant defense in Arabidopsis. We also showed that the reactivation of the endogenousATCOPIA93copy“EVD”, in the presence of bacterial stress, is not only negatively regulated by DNA methylation but also by Polycomb-mediated silencing—a mode of repression typically found at protein-coding and microRNA genes. Interestingly, one of theATCOPIA93-derived soloLTRs is located upstream of the disease resistance geneRPP4and is devoid of either DNA methylation or H3K27m3 marks. Through loss-of-function experiments, we demonstrated that this soloLTR is required for proper expression ofRPP4during plant defense, thus linking the responsiveness ofATCOPIA93to biotic stress and the co-option of its LTR for plant immunity.

scholarly journals Huntingtin and the Synapse

2021 ◽  
Vol 15 ◽  
Author(s):  
Jessica C. Barron ◽  
Emily P. Hurley ◽  
Matthew P. Parsons
Keyword(s):  
Trinucleotide Repeat ◽  
Treatment Strategies ◽  
Retrograde Transport ◽  
Synaptic Function ◽  
Adult Brain ◽  
Brain Diseases ◽  
Monogenic Disease ◽  
Vesicle Recycling ◽  
Receptor Localization ◽  
Synaptic Neurotransmission

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.

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