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

Abstract

The K+/Clco-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 -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 homeostasis and viability that lead to epileptogenesis, remains to be assessed. Here, we have investigated these issues using conditional ablation of SLC12A5 gene expression with AAVs. Decreasing KCC2 expression resulted in the rapid activation of the extrinsic apoptotic pathway, but not the intrinsic pathway, in mature hippocampal neurons, in vitro and in vivo. Intriguingly, direct pharmacological inhibition of KCC2 in mature hippocampal neurons was also sufficient to activate the apoptotic pathway within 10 minutes. Finally, ablating KCC2 expression during neuronal development had no discernable effects on neuronal development, viability and apoptosis. However, KCC2 was essential for the postnatal development of GABAergic inhibition. Collectively, our results demonstrate that correct KCC2 expression and activity play a critical role in neuronal survival. Perturbed KCC2 activity initiates the extrinsic pathway of apoptosis but has a minimal impact on regulating neuronal development. Thus, increasing KCC2 activity may be a useful strategy to limit neuronal death that underlies epiletogenesis.

The effects of postnatal erythropoietin and nano‐erythropoietin on behavioral alterations by mediating K‐Cl co‐transporter 2 in the valproic acid‐induced rat model of autism

“…The previous studies have approved the relationship between KCC2 downregulation and activation of extrinsic apoptotic pathway. Similar reports also have been published in case of pharmacological blockade of KCC2 and subsequent neuronal death (Di et al., 2020; Kontou et al., 2021).…”