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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 (GABA_A) receptors. The inhibitory activity of GABA_A 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. TGF? expression was also increased after TBI and competitive antagonism of TGF? reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGF? might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGF?, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

SUBMITTER: Wang F

PROVIDER: S-EPMC5368191 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Wang Fushun F Wang Xiaowei X Shapiro Lee A LA Cotrina Maria L ML Liu Weimin W Wang Ernest W EW Gu Simeng S Wang Wei W He Xiaosheng X Nedergaard Maiken M Huang Jason H JH

Brain structure & function 20160901 3

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 i ...[more]

PMID: 27586142

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Project description:Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation of fyn or tau appears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO (fyn -/-), tau KO (tau -/-), double knockout (DKO) (fyn -/- / tau -/-), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of the tau -/- and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.

Dataset Information

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

Publications

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

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