Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures

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

doi:10.1523/JNEUROSCI.1769-10.2010

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Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures

Journal article

Open access

Peer reviewed

Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures

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

The Journal of neuroscience, Vol.30(35), pp.11745-11761

09/01/2010

DOI: 10.1523/JNEUROSCI.1769-10.2010

PMCID: PMC3070296

PMID: 20810895

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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 GABA(A) receptor activation from inhibition to excitation assayed by the frequency of action potentials and intracellular Ca(2+) 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.

Animals, Newborn

Recurrence

Neurons - chemistry

Hippocampus - chemistry

Rats

Male

Seizures - metabolism

Rats, Sprague-Dawley

Disease Progression

Hippocampus - metabolism

Animals

Solute Carrier Family 12, Member 2

Time Factors

Chlorides - metabolism

Sodium-Potassium-Chloride Symporters - physiology

Female

Intracellular Fluid - chemistry

Mice

Neurons - metabolism

Hippocampus - physiology

Chlorides - physiology

Intracellular Fluid - metabolism

Details

Title: Subtitle: Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures
Creators: Volodymyr I Dzhala - Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Kishore V Kuchibhotla
Joseph C Glykys
Kristopher T Kahle
Waldemar B Swiercz
Guoping Feng
Thomas Kuner
George J Augustine
Brian J Bacskai
Kevin J Staley
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.30(35), pp.11745-11761
Publisher: United States
DOI: 10.1523/JNEUROSCI.1769-10.2010
PMID: 20810895
PMCID: PMC3070296
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: R01 NS040109-08S1 / NINDS NIH HHS R01 NS040109-08 / NINDS NIH HHS EB000768 / NIBIB NIH HHS R01 NS040109-10 / NINDS NIH HHS R01 NS040109 / NINDS NIH HHS R01 NS040109-09 / NINDS NIH HHS R01 EB000768 / NIBIB NIH HHS NS580752 / NINDS NIH HHS NS 40109-06 / NINDS NIH HHS
Language: English
Date published: 09/01/2010
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984020900102771

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