RT Journal Article
SR Electronic
T1 KCC2 is required for the survival of mature neurons but not for their development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.29.360875
DO 10.1101/2020.10.29.360875
A1 Georgina Kontou
A1 Josephine Ng
A1 Ross Andrew Cardarelli
A1 Jack Howden
A1 Catherine Choi
A1 Qiu Ren
A1 Josef Kittler
A1 Nicholas Brandon
A1 Stephen J. Moss
A1 Joshua L. Smalley
YR 2020
UL http://biorxiv.org/content/early/2020/10/29/2020.10.29.360875.abstract
AB The K+/Cl– co-transporter 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 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 resulted in the rapid activation of the extrinsic apoptotic pathway, in mature hippocampal neurons. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization or dendritic structure. However ablating KCC2 expression in immature neurons was sufficient to prevent 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 loss of KCC2 function. In contrast KCC2 appears to play a minimal role in mediating neuronal development or architecture.AAVAdeno-associated virusDIVdays in vitroGABAARγ-aminobutyric acid type A receptorsGFPgreen fluorescent proteinKCC2K+/Cl− co-transporter 2KOknock-outPARPpoly (ADP-ribose) polymerase (PARP)TLEtemporal lobe epilepsy