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

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Sierra-Torre , V , Plaza-Zabala , A , Bonifazi , P , Abiega , O , Diaz-Aparicio , I , Tegelberg , S , Lehesjoki , A-E , Valero , J & Sierra , A 2020 , ' Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy ' , Epilepsia , vol. 61 , no. 11 , pp. 2593-2608 . https://doi.org/10.1111/epi.16692

Title: Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy
Author: Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Bonifazi, Paolo; Abiega, Oihane; Diaz-Aparicio, Irune; Tegelberg, Saara; Lehesjoki, Anna-Elina; Valero, Jorge; Sierra, Amanda
Contributor organization: Medicum
Anna-Elina Lehesjoki / Principal Investigator
Department of Medical and Clinical Genetics
University of Helsinki
HUS Helsinki and Uusimaa Hospital District
Date: 2020-11
Language: eng
Number of pages: 16
Belongs to series: Epilepsia
ISSN: 0013-9580
DOI: https://doi.org/10.1111/epi.16692
URI: http://hdl.handle.net/10138/325007
Abstract: 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 ofCstbknockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduceCstbexpression, 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 ofCstbKO 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 inCstbKO 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) inCstb-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 forCstbKO 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 inCstbKO 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.
Subject: apoptosis
epilepsy
hippocampus
microglia
phagocytosis
seizures
PROGRESSIVE MYOCLONUS EPILEPSY
CYSTATIN-B
MOUSE MODEL
APOPTOTIC CELLS
CSTB(-/-) MOUSE
ACTIVATION
MUTATION
BRAIN
INFLAMMATION
EXPRESSION
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by_nc
Usage restriction: openAccess
Self-archived version: publishedVersion


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