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Environmental enrichment prevents A? oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

ABSTRACT: As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble A? oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble A? oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by A? oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human A? oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of A? accumulation during human brain aging.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7243177 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

Wei Zhiyun Z Meng Xingjun X El Fatimy Rachid R Sun Bowen B Mai Dongmei D Zhang Junfang J Arora Ramil R Zeng Ailiang A Xu Pingyi P Qu Shaogang S Krichevsky Anna M AM Selkoe Dennis J DJ Li Shaomin S

Neurobiology of disease 20191024

As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanis ...[more]

PMID: 31669733

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Project description:Onset and progression of neurodegenerative disorders, including synucleinopathies such as Parkinson's disease, have been associated with various environmental factors. A highly compelling association from a therapeutic point of view has been found between a physically active lifestyle and a significantly reduced risk for Parkinson's disease. Mimicking such conditions in animal models by promoting physical activity, social interactions, and novel surroundings yields in a so-called enriched environment known to enhance adult neurogenesis, increase synaptic plasticity, and decelerate neuronal loss. Yet, the genes that connect beneficial environmental cues to the genome and delay disease-related symptoms have remained largely unclear. To identify such mediator genes, we used a 2 × 2 factorial design opposing genotype and environment. Specifically, we compared wildtype to transgenic mice overexpressing human SNCA, a key gene in synucleinopathies encoding alpha-synuclein, and housed them in a standard and enriched environment from weaning to 12 months of age before profiling their hippocampal transcriptome using RNA-sequencing. Under standard environmental conditions, differentially expressed genes were overrepresented for calcium ion binding, membrane, synapse, and other Gene Ontology terms previously linked to alpha-synuclein biology. Upregulated genes were significantly enriched for genes attributed to astrocytes, microglia, and oligodendrocytes. These disturbances in gene activity were accompanied by reduced levels of several presynaptic proteins and the immediate early genes EGR1 and NURR1. Intriguingly, housing transgenic animals in the enriched environment prevented most of these perturbations in gene activity. In addition, a sustained activation specifically in transgenic animals housed in enriched conditions was observed for several immediate early genes including Egr1, Nr4a2/Nurr1, Arc, and Homer1a. These findings suggest a compensatory mechanism through an enriched environment-activated immediate early gene network that prevented most disturbances induced by alpha-synuclein overexpression. This regulatory framework might harbor attractive targets for novel therapeutic approaches that mimic beneficial environmental stimuli.

Project description:Environmental enrichment (EE) is a therapeutic paradigm that consists of complex combinations of physical, cognitive, and social stimuli. The mechanisms underlying EE-mediated synaptic plasticity have yet to be fully elucidated. In this study, we investigated the effects of EE on synaptic vesicle-associated proteins and whether the expression of these proteins is related to behavioral outcomes. A total of 44 CD-1® (ICR) mice aged 6 weeks were randomly assigned to either standard cages or EE (N = 22 each). Rotarod and ladder walking tests were then performed to evaluate motor function. To identify the molecular mechanisms underlying the effects of EE, we assessed differentially expressed proteins (DEPs) in the striatum by proteomic analysis. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were conducted to validate the expressions of these proteins. In the behavioral assessment, EE significantly enhanced performance on the rotarod and ladder walking tests. A total of 116 DEPs (54 upregulated and 62 downregulated proteins) were identified in mice exposed to EE. Gene ontology (GO) analysis demonstrated that the upregulated proteins in EE mice were primarily related to biological processes of synaptic vesicle transport and exocytosis. The GO terms for these biological processes commonly included Synaptic vesicle glycoprotein 2B (SV2B), Rabphilin-3A, and Piccolo. The qRT-PCR and western blot analyses revealed that EE increased the expression of SV2B, Rabphilin-3A and Piccolo in the striatum compared to the control group. Immunohistochemistry showed that the density of Piccolo in the vicinity of the subventricular zone was significantly increased in the EE mice compared with control mice. In conclusion, EE upregulates proteins associated with synaptic vesicle transport and exocytosis such as SV2B, Rabphilin-3A and Piccolo in the striatum. These upregulated proteins may be responsible for locomotor performance improvement, as shown in rotarod and ladder walking tests. Elucidation of these changes in synaptic protein expression provides new insights into the mechanism and potential role of EE.

Project description:Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble A? oligomers (oA?) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oA?-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNF?) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oA? extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oA?, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.Environmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human A? oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.

Project description:BackgroundThe hypothalamus plays a key role in the stress response. While early life stress (ELS) increases susceptibility to psychiatric disorders including major depressive disorder (MDD), acute stress during adulthood can also precipitate MDD after ELS.AimHere, we tested the expression of miRNAs following ELS and susceptibility to depression-like behavior and whether sex or acute stress exacerbates this response. We also tested whether environmental enrichment (Enr) promotes early life and adult behavioral stress resilience and its effect on hypothalamic miRNA and gene expression. Following rat maternal separation (MS) as an ELS model, Enr from weaning through adulthood, and restraint (RS) as acute adult stress, we tested both animal behavior and miRNA expression in the hypothalamus. Target genes and their enrichment and ontology were analyzed using bioinformatic tools. Target gene expression changes were tested using qPCR, and miRNA promoter methylation was studied using methylated-DNA immunoprecipitation qPCR.ResultsMS, Enr, RS, and sex altered hypothalamic miRNAs, including several previously reported in MS literature: miRs-29, - 124, - 132, - 144, - 504. Sex had a significant effect on the greatest number of miRNAs. Also, Enr reversed downregulation of miR-29b-1-5p and -301b-3p in MS. qPCR showed that MAPK6 and MMP19, targets of miR-301b-3p, were upregulated in MS and reversed by Enr. Additionally, miR-219a was hypermethylated in MS coinciding with decreased miR-219a expression.ConclusionsThis study found that sex plays a critical role in the hypothalamic miRNA response to both ELS and acute stress, with males expressing greater changes following postnatal stress. Moreover, enrichment significantly altered behavior as well as hypothalamic miRNA expression and their gene targets. Because of its role as the initiator of the autonomic stress response and connection to hedonic and motivational behavior, the hypothalamic miRNA landscape may significantly alter both the short and long-term behavioral response to stress.

Dataset Information

Environmental enrichment prevents A? oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

Publications

Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways.

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