Blocking TNFα-driven astrocyte purinergic signaling restores normal synaptic activity in epilepsy
2018
Аутори:
Nikolić, LjiljanaShen, Weida
Nobili, Paola
Virenque, Anaïs
Ulmann, Lauriane
Audinat, Etienne
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2018 Wiley Periodicals, Inc.
Метаподаци
Приказ свих података о документуАпстракт:
Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes partici- pates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release. Here we tested whether TNFα controls abnormal astrocyte glutamate signal- ing in epilepsy and through which mechanism. Combining Ca2+ imaging, optogenetics, and elec- trophysiology, we report that TNFα triggers a Ca2+-dependent glutamate release from astrocytes that boosts excitatory synaptic activity in the hippocampus through a mechanism involving autocrine activation of P2Y1 receptors by astrocyte-derived ATP/ADP. In a mouse model of temporal lobe epilepsy, such TNFα-driven astrocytic purinergic signaling is perma- nently active, promotes glial glutamate release, and drives abnormal synaptic activity in the hip- pocampus. Blocking this pathway by inhibiting P2Y1 receptors restores normal excitatory synaptic activity in the inflamed hippocampus. Our findings indicate that targeting the coupling of TNFα with astrocyte purinergic signaling may be a therapeutic strategy for reducing glial glu- tamate release and normalizing synaptic activity in epilepsy.
Кључне речи:
calcium signaling; cytokine; disease; gliotransmission; inflammation; optogeneticsИзвор:
Glia, 2018, 66, 12, 2673-2683Финансирање / пројекти:
- Fondation pour la Recherche Médicale (FRM: DEQ20140329488)
- European Union (ERA-NET Neuron BrIE)
- Agence National de la Recherche (ANR-2011-BSV4-004-02)
Повезане информације:
- Друга верзија
https://radar.ibiss.bg.ac.rs/handle/123456789/5515
DOI: 10.1002/glia.23519
ISSN: 0894-1491
PubMed: 30394583