NKCC1 transporter facilitates seizures in the developing brain

@article{Dzhala2005NKCC1TF,
  title={NKCC1 transporter facilitates seizures in the developing brain},
  author={Volodymyr I. Dzhala and Delia Talos and Dan Sdrulla and Audrey C. Brumback and Gregory C. Mathews and Tim A Benke and Eric Delpire and Frances E. Jensen and Kevin J. Staley},
  journal={Nature Medicine},
  year={2005},
  volume={11},
  pages={1205-1213}
}
During development, activation of Cl−-permeable GABAA receptors (GABAA-R) excites neurons as a result of elevated intracellular Cl− levels and a depolarized Cl− equilibrium potential (ECl). GABA becomes inhibitory as net outward neuronal transport of Cl− develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na+-K+-2Cl… 
Thermodynamic Regulation of NKCC1-Mediated Cl− Cotransport Underlies Plasticity of GABAA Signaling in Neonatal Neurons
TLDR
Activity-induced changes in Na+-K+-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA, and require an inducible, active mechanism of chloride accumulation.
NKCC1 activity modulates formation of functional inhibitory synapses in cultured neocortical neurons
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The results suggest that the uptake of Cl− by NKCC1 affects the development of inhibitory synapses by promoting a depolarizing GABA‐mediated response.
Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures
TLDR
The results demonstrate a novel mechanism by which seizure activity leads to [Cl−]i accumulation, thereby increasing the probability of subsequent seizures, and provides a potential mechanism for the early crescendo phase of neonatal seizures.
Altered Neuronal Chloride Homeostasis and Excitatory GABAergic Signaling in Human Temporal Lobe Epilepsy
TLDR
The data suggest that changes in the relative expression of NKCC1 and KCC2 in neurons having aberrant GABAergic hyperinnervation may contribute to epileptiform activity in the subicular regions adjacent to sclerotic areas of the hippocampus.
Compensatory Enhancement of Intrinsic Spiking upon NKCC1 Disruption in Neonatal Hippocampus
TLDR
It is shown that genetic as well as pharmacologically induced loss of NKCC1-dependent excitatory actions of GABA results in a dramatic compensatory increase in the intrinsic excitability of glutamatergic neurons, pointing to powerful homeostatic regulation of neuronal activity in the developing hippocampal circuitry.
Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory.
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  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
The anomalous expression of both Cl(-) transporters, NKCC1 and KCC2 [corrected] in TLE hippocampal subiculum probably causes altered Cl(+) transport in the "epileptic" neurons, as revealed in the microtransplanted Xenopus oocytes, and renders GABA aberrantly "exciting," a feature that may contribute to the precipitation of epileptic seizures.
Regulation of GABA Equilibrium Potential by mGluRs in Rat Hippocampal CA1 Neurons
TLDR
Results indicate that TBS induces a negative shift in EGABA in juvenile hippocampal neurons but a positive shift in neonatal hippocampusal neurons via corresponding changes in KCC2 and NKCC1 expressions, respectively.
Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function
TLDR
The potential for NKCC1 and KCC2 to be therapeutic targets for the development of novel antiepileptic drugs is explored and its implications on the treatment of epilepsy are explored.
Alterations in the expression of neuronal chloride transporters may contribute to schizophrenia
  • H. Kalkman
  • Biology, Psychology
    Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • 2011
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