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 language | English (US) |
|---|---|
| Pages (from-to) | 11745-11761 |
| Number of pages | 17 |
| Journal | Journal of Neuroscience |
| Volume | 30 |
| Issue number | 35 |
| DOIs | |
| State | Published - Sep 1 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Neuroscience(all)
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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 journal › Article
}
TY - JOUR
T1 - Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures
AU - Dzhala, Volodymyr I.
AU - Kuchibhotla, Kishore
AU - Glykys, Joseph C.
AU - Kahle, Kristopher T.
AU - Swiercz, Waldemar B.
AU - Feng, Guoping
AU - Kuner, Thomas
AU - Augustine, George J.
AU - Bacskai, Brian J.
AU - Staley, Kevin J.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77956234437&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956234437&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1769-10.2010
DO - 10.1523/JNEUROSCI.1769-10.2010
M3 - Article
C2 - 20810895
AN - SCOPUS:77956234437
VL - 30
SP - 11745
EP - 11761
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 35
ER -