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Bestrophin1‐mediated tonic GABA release from reactive astrocytes prevents the development of seizure‐prone network in kainate‐injected hippocampi
Author(s) -
Pandit Sudip,
Neupane Chiranjivi,
Woo Junsung,
Sharma Ramesh,
Nam MinHo,
Lee GyuSeung,
Yi MinHee,
Shin Nara,
Kim Dong Woon,
Cho Hyunsill,
Jeon Byeong Hwa,
Kim HyunWoo,
Lee C. Justin,
Park Jin Bong
Publication year - 2020
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23762
Subject(s) - kainic acid , tonic (physiology) , kainate receptor , neuroscience , epilepsy , astrocyte , gamma aminobutyric acid , status epilepticus , gabaa receptor , biology , glutamate receptor , central nervous system , receptor , ampa receptor , biochemistry
Tonic extrasynaptic GABA A receptor (GABA A R) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA‐permeable Bestrophin‐1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)‐induced epileptic mice. Astrocyte‐specific Best1 over‐expression in KA‐injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi, serving as a good therapeutic target against altered E/I balance in epileptic seizures.