Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures

Volodymyr I. Dzhala, Kishore Kuchibhotla, Joseph C. Glykys, Kristopher T. Kahle, Waldemar B. Swiercz, Guoping Feng, Thomas Kuner, George J. Augustine, Brian J. Bacskai, Kevin J. Staley

Research output: Contribution to journalArticle

Abstract

Seizures induce excitatory shifts in the reversal potential for GABA A-receptor-mediated responses, which may contribute to the intractability of electro-encephalographic seizures and preclude the efficacy of widely used GABAergic anticonvulsants such as phenobarbital. We now report that, in intact hippocampi prepared from neonatal rats and transgenic mice expressing Clomeleon, recurrent seizures progressively increase the intracellular chloride concentration ([Cl-]i ) assayed by Clomeleon imaging and invert the net effect of GABAA receptor activation from inhibition to excitation assayed by the frequency of action potentials and intracellular Ca2+ transients. These changes correlate with increasing frequency of seizure-like events and reduction in phenobarbital efficacy. The Na+-K+-2Cl- (NKCC1) cotransporter blocker bumetanide inhibited seizure-induced neuronal Cl - accumulation and the consequent facilitation of recurrent seizures. Our results demonstrate a novel mechanism by which seizure activity leads to [Cl-]i accumulation, thereby increasing the probability of subsequent seizures. This provides a potential mechanism for the early crescendo phase of neonatal seizures.

Original languageEnglish (US)
Pages (from-to)11745-11761
Number of pages17
JournalJournal of Neuroscience
Volume30
Issue number35
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

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Chlorides
Seizures
GABA-A Receptors
Phenobarbital
Member 2 Solute Carrier Family 12
Bumetanide
Anticonvulsants
Transgenic Mice
Action Potentials
Hippocampus

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dzhala, V. I., Kuchibhotla, K., Glykys, J. C., Kahle, K. T., Swiercz, W. B., Feng, G., ... Staley, K. J. (2010). Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures. Journal of Neuroscience, 30(35), 11745-11761. https://doi.org/10.1523/JNEUROSCI.1769-10.2010

Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures. / Dzhala, Volodymyr I.; Kuchibhotla, Kishore; Glykys, Joseph C.; Kahle, Kristopher T.; Swiercz, Waldemar B.; Feng, Guoping; Kuner, Thomas; Augustine, George J.; Bacskai, Brian J.; Staley, Kevin J.

In: Journal of Neuroscience, Vol. 30, No. 35, 01.09.2010, p. 11745-11761.

Research output: Contribution to journalArticle

Dzhala, VI, Kuchibhotla, K, Glykys, JC, Kahle, KT, Swiercz, WB, Feng, G, Kuner, T, Augustine, GJ, Bacskai, BJ & Staley, KJ 2010, 'Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures', Journal of Neuroscience, vol. 30, no. 35, pp. 11745-11761. https://doi.org/10.1523/JNEUROSCI.1769-10.2010
Dzhala, Volodymyr I. ; Kuchibhotla, Kishore ; Glykys, Joseph C. ; Kahle, Kristopher T. ; Swiercz, Waldemar B. ; Feng, Guoping ; Kuner, Thomas ; Augustine, George J. ; Bacskai, Brian J. ; Staley, Kevin J. / Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 35. pp. 11745-11761.
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