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      Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice

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          Abstract

          Neurological complications affecting the central nervous system have been reported in adult patients infected by Zika virus (ZIKV) but the underlying mechanisms remain unknown. Here, we report that ZIKV replicates in human and mouse adult brain tissue, targeting mature neurons. ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation and induces memory impairment in adult mice. TNF-α upregulation, microgliosis and upregulation of complement system proteins, C1q and C3, are induced by ZIKV infection. Microglia are found to engulf hippocampal presynaptic terminals during acute infection. Neutralization of TNF-α signaling, blockage of microglial activation or of C1q/C3 prevent synapse and memory impairment in ZIKV-infected mice. Results suggest that ZIKV induces synapse and memory dysfunction via aberrant activation of TNF-α, microglia and complement. Our findings establish a mechanism by which ZIKV affects the adult brain, and point to the need of evaluating cognitive deficits as a potential comorbidity in ZIKV-infected adults.

          Abstract

          Here, using ex-vivo human adult cortical tissue and a mouse model, the authors investigate the functional consequences of Zika virus (ZIKV) infection in the adult brain, and show that ZIKV causes synapse damage and altered brain function that impacts cognition via activation of innate and inflammatory factors.

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          Most cited references39

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          Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics.

          The development of the living acute brain slice preparation for analyzing synaptic function roughly a half century ago was a pivotal achievement that greatly influenced the landscape of modern neuroscience. Indeed, many neuroscientists regard brain slices as the gold-standard model system for detailed cellular, molecular, and circuitry level analysis and perturbation of neuronal function. A critical limitation of this model system is the difficulty in preparing slices from adult and aging animals, and over the past several decades few substantial methodological improvements have emerged to facilitate patch clamp analysis in the mature adult stage. In this chapter we describe a robust and practical protocol for preparing brain slices from mature adult mice that are suitable for patch clamp analysis. This method reduces swelling and damage in superficial layers of the slices and improves the success rate for targeted patch clamp recordings, including recordings from fluorescently labeled populations in slices derived from transgenic mice. This adult brain slice method is suitable for diverse experimental applications, including both monitoring and manipulating neuronal activity with genetically encoded calcium indicators and optogenetic actuators, respectively. We describe the application of this adult brain slice platform and associated methods for screening kinetic properties of Channelrhodopsin (ChR) variants expressed in genetically defined neuronal subtypes.
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            Molecular pathways to neurodegeneration.

            The molecular bases underlying the pathogenesis of neurodegenerative diseases are gradually being disclosed. One problem that investigators face is distinguishing primary from secondary events. Rare, inherited mutations causing familial forms of these disorders have provided important insights into the molecular networks implicated in disease pathogenesis. Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic insult, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis and failure of axonal and dendritic transport represent unifying events in many slowly progressive neurodegenerative disorders.
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              Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation.

              Zika virus (ZIKV)-related neuropathology is an important global health concern. Several studies have shown that ZIKV can infect neural stem cells in the developing brain, but infection in the adult brain has not been examined. Two areas in the adult mouse brain contain neural stem cells: the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus. Here, using 6-week-old mice triply deficient in interferon regulatory factor (IRF) as a model, we show that blood-borne ZIKV administration can lead to pronounced evidence of ZIKV infection in these adult neural stem cells, leading to cell death and reduced proliferation. Our data therefore suggest that adult as well as fetal neural stem cells are vulnerable to ZIKV neuropathology. Thus, although ZIKV is considered a transient infection in adult humans without marked long-term effects, there may in fact be consequences of exposure in the adult brain.
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                Author and article information

                Contributors
                claudia@pharma.ufrj.br
                dapoian@bioqmed.ufrj.br
                ferreira@bioqmed.ufrj.br
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                5 September 2019
                5 September 2019
                2019
                : 10
                : 3890
                Affiliations
                [1 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, School of Pharmacy, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [2 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Institute of Biomedical Sciences, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [3 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Institute of Microbiology Paulo de Goes, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [4 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Institute of Medical Biochemistry Leopoldo de Meis, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [5 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Institute of Biophysics Carlos Chagas Filho, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [6 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, , Federal University of Rio de Janeiro, ; Rio de Janeiro, RJ 21944-590 Brazil
                [7 ]ISNI 0000 0004 1936 8331, GRID grid.410356.5, Graduate Program in Neurology, , Federal University of Rio de Janeiro State, Queen’s University, ; Kingston, ON Canada
                [8 ]ISNI 0000 0004 1936 8331, GRID grid.410356.5, Centre for Neuroscience Studies & Department of Psychiatry, , Queen’s University, ; Kingston, ON Canada
                Author information
                http://orcid.org/0000-0002-1663-8346
                http://orcid.org/0000-0002-3814-999X
                http://orcid.org/0000-0002-0335-2541
                http://orcid.org/0000-0002-2040-3224
                http://orcid.org/0000-0002-7561-8150
                http://orcid.org/0000-0002-0801-6993
                http://orcid.org/0000-0002-3360-2740
                http://orcid.org/0000-0002-7027-3851
                http://orcid.org/0000-0001-9570-7428
                http://orcid.org/0000-0001-8358-0589
                http://orcid.org/0000-0001-5684-4788
                http://orcid.org/0000-0002-3969-704X
                http://orcid.org/0000-0001-7160-9866
                Article
                11866
                10.1038/s41467-019-11866-7
                6728367
                31488835
                09ee0cd3-d94d-4813-881b-11336598871e
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 May 2018
                : 31 July 2019
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                © The Author(s) 2019

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                virology,diseases of the nervous system,learning and memory,molecular neuroscience

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