Impaired microglial phagocytosis promotes seizure development
In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 02. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bosco, Dale B [VerfasserIn] |
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| Anmerkungen: |
Date Revised 01.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.12.31.573794 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367510855 |
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| 100 | 1 | |a Bosco, Dale B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Impaired microglial phagocytosis promotes seizure development |
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| 500 | |a Date Revised 01.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Kremen, Vaclav |e verfasserin |4 aut | |
| 700 | 1 | |a Haruwaka, Koichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Shunyi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lingxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Ebner, Blake A |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Jiaying |e verfasserin |4 aut | |
| 700 | 1 | |a Dheer, Aastha |e verfasserin |4 aut | |
| 700 | 1 | |a Perry, Jadyn F |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Manling |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Aivi T |e verfasserin |4 aut | |
| 700 | 1 | |a Worrell, Gregory A |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Long-Jun |e verfasserin |4 aut | |
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