Dataset Information

KCC2 activity is critical in limiting the onset and severity of status epilepticus.

ABSTRACT: The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.

SUBMITTER: Silayeva L

PROVIDER: S-EPMC4371976 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundCurrent prognostic scores for status epilepticus (SE) may not be adequate for patients in ICU who usually have more severe systemic conditions or more refractory episodes of SE. We aimed to compare the prognostic performance of two SE scores, Status Epilepticus Severity Score (STESS) and Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) score, with four systemic severity scores, Acute Physiology and Chronic Health Evaluation 2 (APACHE-2), Simplified Acute Physiology Score 2 (SAPS-2), Sequential Organ Failure Assessment (SOFA) score, and Inflammation, Nutrition, Consciousness, Neurologic function and Systemic condition (INCNS) score in critically ill patients with SE.MethodsThis retrospective observational study of a prospectively identified SE cohort was conducted in the ICU at a tertiary-care center. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and associations with outcomes of STESS, EMSE, INCNS, APACHE-2, SAPS-2, and SOFA score for the prediction of in-hospital mortality and no return to baseline condition were assessed.ResultsBetween January 2015 and December 2020, 166 patients with SE in ICU were included in the study. In predicting in-hospital death, APACHE-2 (0.72), SAPS-2 (0.73), and SOFA score (0.71) had higher AUCs than STESS (0.58) and EMSE (0.69). In predicting no return to baseline condition, the AUC of APACHE-2 (0.75) was the highest, and the AUC of INCNS (0.55) was the lowest. When the specificity approached 90%, the sensitivity values of these scores were not quite acceptable (< 40%). Neither SE scores nor systemic severity scores had desirable prognostic power. In the multivariate logistic regression analyses, the best combinations of scores always included at least one or more systemic severity scores.ConclusionsSTESS and EMSE were insufficient in outcome prediction for SE patients in ICU, and EMSE was marginally better than STESS. Systemic illness matters in ICU patients with SE, and SE scores should be modified to achieve better accuracy in this severely ill population. This study mostly refers to severely ill patients in the ICU.

Dataset Information

KCC2 activity is critical in limiting the onset and severity of status epilepticus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets