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Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy

OBJECTIVE: Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a m...

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Autores principales: Sierra‐Torre, Virginia, Plaza‐Zabala, Ainhoa, Bonifazi, Paolo, Abiega, Oihane, Díaz‐Aparicio, Irune, Tegelberg, Saara, Lehesjoki, Anna‐Elina, Valero, Jorge, Sierra, Amanda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756777/
https://www.ncbi.nlm.nih.gov/pubmed/32940364
http://dx.doi.org/10.1111/epi.16692
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author Sierra‐Torre, Virginia
Plaza‐Zabala, Ainhoa
Bonifazi, Paolo
Abiega, Oihane
Díaz‐Aparicio, Irune
Tegelberg, Saara
Lehesjoki, Anna‐Elina
Valero, Jorge
Sierra, Amanda
author_facet Sierra‐Torre, Virginia
Plaza‐Zabala, Ainhoa
Bonifazi, Paolo
Abiega, Oihane
Díaz‐Aparicio, Irune
Tegelberg, Saara
Lehesjoki, Anna‐Elina
Valero, Jorge
Sierra, Amanda
author_sort Sierra‐Torre, Virginia
collection PubMed
description OBJECTIVE: Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB). METHODS: We used confocal imaging and stereology‐based quantification of apoptosis and phagocytosis of the hippocampus of Cstb knockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduce Cstb expression, and a virtual three‐dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons. RESULTS: Microglial phagocytosis was impaired in the hippocampus of Cstb KO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present in Cstb KO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) in Cstb‐deficient mice were at close proximity to active cFos(+) neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos(+) neurons was specific for Cstb KO mice. SIGNIFICANCE: These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction in Cstb KO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.
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spelling pubmed-77567772020-12-28 Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy Sierra‐Torre, Virginia Plaza‐Zabala, Ainhoa Bonifazi, Paolo Abiega, Oihane Díaz‐Aparicio, Irune Tegelberg, Saara Lehesjoki, Anna‐Elina Valero, Jorge Sierra, Amanda Epilepsia Full‐length Original Research OBJECTIVE: Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB). METHODS: We used confocal imaging and stereology‐based quantification of apoptosis and phagocytosis of the hippocampus of Cstb knockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduce Cstb expression, and a virtual three‐dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons. RESULTS: Microglial phagocytosis was impaired in the hippocampus of Cstb KO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present in Cstb KO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) in Cstb‐deficient mice were at close proximity to active cFos(+) neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos(+) neurons was specific for Cstb KO mice. SIGNIFICANCE: These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction in Cstb KO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis. John Wiley and Sons Inc. 2020-09-17 2020-11 /pmc/articles/PMC7756777/ /pubmed/32940364 http://dx.doi.org/10.1111/epi.16692 Text en © 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Full‐length Original Research
Sierra‐Torre, Virginia
Plaza‐Zabala, Ainhoa
Bonifazi, Paolo
Abiega, Oihane
Díaz‐Aparicio, Irune
Tegelberg, Saara
Lehesjoki, Anna‐Elina
Valero, Jorge
Sierra, Amanda
Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title_full Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title_fullStr Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title_full_unstemmed Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title_short Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
title_sort microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
topic Full‐length Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756777/
https://www.ncbi.nlm.nih.gov/pubmed/32940364
http://dx.doi.org/10.1111/epi.16692
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