Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures
- Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures
- Dzhala, Volodymyr I.; Kuchibhotla, Kishore V.; Glykys, Joseph C; Kahle, Kristopher T.; Swiercz, Waldemar B.; Feng, Guoping; Kuner, Thomas; 조지어거스틴; Bacskai, Brian J; Staley, Kevin J
- GABA; Phenobarbital; Clomeleon; action potential; epileptiform activity; hippocampus
- Issue Date
- Journal of neuroscience
- VOL 30 , NO 35, 11745-11761
- Seizures induce excitatory shifts in the reversal potential for GABAA-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 ofGABAA
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.
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