KCC2 is required for the survival of mature neurons but not for their development
| Autor: | Shu Fun Josephine Ng, Jack H. Howden, Christopher E. Bope, Miguel A. Rodriguez Santos, Jake S. Dengler, Matt R. Kelley, Qiu Ren, Paul Davies, Ross A. Cardarelli, Catherine Choi, Josef T. Kittler, Joshua L. Smalley, Stephen J. Moss, Georgina Kontou, Nicholas J. Brandon |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Programmed cell death Neurogenesis KCC2 Poly ADP ribose polymerase Primary Cell Culture TLE temporal lobe epilepsy Apoptosis Biochemistry Epileptogenesis Mice 03 medical and health sciences chemistry.chemical_compound AAV adeno-associated virus Chlorides Receptors GABA Seizures Animals TTX tetrodotoxin Receptor Molecular Biology gamma-Aminobutyric Acid GFP green fluorescent protein Mice Knockout Neurons KO knockout Symporters 030102 biochemistry & molecular biology PARP poly (ADP-ribose) polymerase (PARP) Cell Biology KCC2 K+/Cl− cotransporter 2 DIV days in vitro Cell biology Mice Inbred C57BL cell death 030104 developmental biology nervous system chemistry Potassium Tetrodotoxin Female extrinsic pathway Cotransporter GABAAR γ-aminobutyric acid type A receptors Intracellular Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|