NKCC1 transporter facilitates seizures in the developing brain.
During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). 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(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.
Dzhala
Volodymyr I
VI
Department of Neurology, School of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262, USA.
Talos
Delia M
DM
Sdrulla
Dan A
DA
Brumback
Audrey C
AC
Mathews
Gregory C
GC
Benke
Timothy A
TA
Delpire
Eric
E
Jensen
Frances E
FE
Staley
Kevin J
KJ
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D002034:Bumetanide / Q000494:pharmacology / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000502:physiology*; D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use*; D004569:Electroencephalography; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007608:Kainic Acid; D008564:Membrane Potentials / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics; D064506:Solute Carrier Family 12, Member 2
D000927:Anticonvulsants; D004232:Diuretics; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D007608:Kainic Acid; D010634:Phenobarbital