NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility

Abstract

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl−, which is achieved by the opposing regulation of Na+–K+–Cl− cotransporter 1 (NKCC1) and K+–Cl−–cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl− concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-016-1292-z) contains supplementary material, which is available to authorized users.

KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

“…In addition, our data show that depolarized E GABA upon KCC2 suppression is fully compensated by depolarized V rest , such that KCC2 knockdown neurons are more excitable, although GABA signaling remains inhibitory. Depolarizing GABAergic responses may then require further depolarization of E GABA , for instance through concomitant upregulation of the NKCC1 transporter, as observed in temporal lobe epilepsy models (Kourdougli et al, 2017;Wang et al, 2017) as well as in the cortex and hippocampus from epileptic patients (Pallud et al, 2014;Sen et al, 2007).…”

Antisecretory Factor May Reduce ICP in Severe TBI—A Case Series

“…The exact mechanism of AF is unknown, but it has been proposed to act by modulation of proteasomes, complement, and myeloid cells (8)(9)(10). A recent report shows that AF inhibits the NKCC1 ion pump; the latter also has been implicated in the evolution of edema in TBI (11,12).…”

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

“…In addition, our data show that depolarized E GABA upon KCC2 suppression is fully compensated by depolarized V rest , such that KCC2 knockdown neurons are more excitable although GABA signaling remains inhibitory. Depolarizing GABAergic responses may then require further depolarization of E GABA , for instance through concomitant upregulation of the NKCC1 transporter, as observed in temporal lobe epilepsy models 20,75 as well as in the cortex and hippocampus from epileptic patients 71,76 .…”