A single seizure episode leads to rapid functional activation of KCC2 in the neonatal rat hippocampus.
Functional expression of the K-Cl cotransporter KCC2 in developing central neurons is crucial for the maturation of Cl(-)-dependent, GABA(A) receptor-mediated inhibitory responses. In pyramidal neurons of the rodent hippocampus, GABAergic postsynaptic responses are typically depolarizing and often excitatory during the first postnatal week. Here, we show that a single neonatal seizure episode induced by kainate injection during postnatal days 5-7 results in a fast increase in the Cl(-) extrusion capacity of rat hippocampal CA1 neurons, with a consequent hyperpolarizing shift of the reversal potential of GABA(A)-mediated currents (E(GABA)). A significant increase in the surface expression of KCC2 as well as the alpha2 subunit of the Na-K-ATPase parallels the seizure-induced increase in the Cl(-) extrusion capacity. Exposing hippocampal slices to kainate resulted in a similar increase in the neuronal Cl(-) extrusion and in the surface expression of KCC2. Both effects were blocked by the kinase inhibitor K252a. Hence, in the neonatal hippocampus the overall KCC2 expression level is high enough to promote a rapid functional activation of K-Cl cotransport and a consequent negative shift in E(GABA) close to the adult level. The activity-dependent regulation of KCC2 function and its effect on GABAergic transmission may represent an intrinsic antiepileptogenic mechanism.
Khirug
Stanislav
S
Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland.
Ahmad
Faraz
F
Puskarjov
Martin
M
Afzalov
Ramil
R
Kaila
Kai
K
Blaesse
Peter
P
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation / Q000379:methods; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D000096922:K Cl- Cotransporters
D002227:Carbazoles; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005665:Furosemide; D026121:Indole Alkaloids; D007608:Kainic Acid; D026941:Sodium Channel Blockers; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027981:Symporters; D013779:Tetrodotoxin; D000096922:K Cl- Cotransporters; C049985:staurosporine aglycone
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