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NKCC1 transporter facilitates seizures in the developing brain

Abstract

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 cotransporter (NKCC1) facilitates the accumulation of Cl in neurons. The NKCC1 blocker bumetanide shifted ECl 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 GABAA-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.

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Figure 1: Developmental regulation of NKCC1 and KCC2 in perinatal rat and human cortex.
Figure 2: Effects of phenobarbital on epileptiform activity in the neonatal rat hippocampus in vitro.
Figure 3: Effects of NKCC1 inhibition on EGABA and spontaneous network activity.
Figure 4: Age-dependent effect of bumetanide on epileptiform activity.
Figure 5: Effects of bumetanide in Slc12a2−/− mice.
Figure 6: Bumetanide for neonatal seizure therapy.

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Acknowledgements

This work was supported by the US National Institutes of Health and National Institute of Neurological Disorders and Stroke grants NS34360, NS34700, and NS40109 (to K.J.S.), NS36758 (to E.D.), NS31718 (to F.E.J.), NS38475 (to F.E.J. and D.M.T.) and the Hearst Foundation (to D.M.T.). Some tissue samples were provided by the University of Maryland Brain Tissue Bank for Developmental Disorders, Baltimore, Maryland, USA supported by N01-HD-43368.

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Correspondence to Kevin J Staley.

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Dzhala, V., Talos, D., Sdrulla, D. et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med 11, 1205–1213 (2005). https://doi.org/10.1038/nm1301

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