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Astrocyte-derived TNF and glutamate critically modulate microglia reactivity by methamphetamine

View ORCID ProfileTeresa Canedo, View ORCID ProfileCamila Cabral Portugal, View ORCID ProfileRenato Socodato, View ORCID ProfileJoana Bravo, Tiago Oliveira Almeida, João D. Magalhães, View ORCID ProfileSónia Guerra-Gomes, View ORCID ProfileJoão Filipe Oliveira, View ORCID ProfileNuno Sousa, View ORCID ProfileAna Magalhães, View ORCID ProfileJoão Bettencourt Relvas, View ORCID ProfileTeresa Summavielle
doi: https://doi.org/10.1101/2021.02.22.432170
Teresa Canedo
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
2Faculdade de Medicina da Universidade do Porto (FMUP), Portugal.
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Camila Cabral Portugal
3Glial Cell Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
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  • For correspondence: tsummavi@ibmc.up.pt
Renato Socodato
3Glial Cell Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
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Joana Bravo
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
4Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Portugal
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Tiago Oliveira Almeida
3Glial Cell Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
4Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Portugal
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João D. Magalhães
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
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Sónia Guerra-Gomes
5Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal.
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João Filipe Oliveira
5Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal.
6ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
7IPCA-EST-2Ai, Polytechnic Institute of Cávado and Ave, Applied Artificial Intelligence
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Nuno Sousa
5Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal.
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Ana Magalhães
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
4Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Portugal
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João Bettencourt Relvas
2Faculdade de Medicina da Universidade do Porto (FMUP), Portugal.
3Glial Cell Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
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Teresa Summavielle
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Portugal.
8ESS.PP, Escola Superior de Saúde do Politécnico do Porto, Portugal
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  • For correspondence: tsummavi@ibmc.up.pt
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Abstract

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation that contributes to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders linked to cognitive impairment and neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in human Meth abusers), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a manner dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production or suppressing astrocytic calcium mobilization prevented microglia reactivity and abolished the behavioral phenotype elicited by Meth exposure. Overall, our data indicate that glial crosstalk is critical to relay behavioral alterations caused by acute Meth exposure.

One Sentence Summary Glial crosstalk under methamphetamine exposure

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵Camila Cabral Portugal, Glial Cell Biology Lab, Instituto de Investigação e Inovação em Saúde, Universidade do Porto Rua Alfredo Allen, 208 4200-135 Porto, Portugal, Phone number: +351 220408800 (Ext. 6139) camila.portugal{at}ibmc.up.pt

  • https://drive.google.com/drive/folders/1TbZ-w-1gpjaiGBjS7XnqfAk7u9urapxX?usp=sharing

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Posted February 22, 2021.
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Astrocyte-derived TNF and glutamate critically modulate microglia reactivity by methamphetamine
Teresa Canedo, Camila Cabral Portugal, Renato Socodato, Joana Bravo, Tiago Oliveira Almeida, João D. Magalhães, Sónia Guerra-Gomes, João Filipe Oliveira, Nuno Sousa, Ana Magalhães, João Bettencourt Relvas, Teresa Summavielle
bioRxiv 2021.02.22.432170; doi: https://doi.org/10.1101/2021.02.22.432170
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Astrocyte-derived TNF and glutamate critically modulate microglia reactivity by methamphetamine
Teresa Canedo, Camila Cabral Portugal, Renato Socodato, Joana Bravo, Tiago Oliveira Almeida, João D. Magalhães, Sónia Guerra-Gomes, João Filipe Oliveira, Nuno Sousa, Ana Magalhães, João Bettencourt Relvas, Teresa Summavielle
bioRxiv 2021.02.22.432170; doi: https://doi.org/10.1101/2021.02.22.432170

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