KCC2 is required for the survival of mature neurons but not for their development

The K+/Cl− cotransporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl− levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in...

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Veröffentlicht in:The Journal of biological chemistry 2021-01, Vol.296, p.100364, Article 100364
Hauptverfasser: Kontou, Georgina, Josephine Ng, Shu Fun, Cardarelli, Ross A., Howden, Jack H., Choi, Catherine, Ren, Qiu, Rodriguez Santos, Miguel A., Bope, Christopher E., Dengler, Jake S., Kelley, Matt R., Davies, Paul A., Kittler, Josef T., Brandon, Nicholas J., Moss, Stephen J., Smalley, Joshua L.
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container_start_page 100364
container_title The Journal of biological chemistry
container_volume 296
creator Kontou, Georgina
Josephine Ng, Shu Fun
Cardarelli, Ross A.
Howden, Jack H.
Choi, Catherine
Ren, Qiu
Rodriguez Santos, Miguel A.
Bope, Christopher E.
Dengler, Jake S.
Kelley, Matt R.
Davies, Paul A.
Kittler, Josef T.
Brandon, Nicholas J.
Moss, Stephen J.
Smalley, Joshua L.
description The K+/Cl− cotransporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl− levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally, which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture, we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization, or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture.
doi_str_mv 10.1016/j.jbc.2021.100364
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In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally, which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture, we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization, or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. 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subjects Animals
Apoptosis
cell death
Chlorides - metabolism
extrinsic pathway
Female
gamma-Aminobutyric Acid - metabolism
K Cl- Cotransporters
KCC2
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurogenesis - drug effects
Neurons - metabolism
Neurons - physiology
Potassium - metabolism
Primary Cell Culture
Receptors, GABA - metabolism
Seizures
Symporters - metabolism
Symporters - physiology
title KCC2 is required for the survival of mature neurons but not for their development
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