Neonatal Seizures: Is a Novel, Mechanism-Based Treatment Finally on the Horizon?

Abstract

NKCC1 Transporter Facilitates Seizures in the Developing Brain Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ Nat Med 2005;11(11):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– 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. Depolarizing GABA Acts on Intrinsically Bursting Pyramidal Neurons to Drive Giant Depolarizing Potentials in the Immature Hippocampus Sipilä ST, Huttu K, Soltesz I, Voipio J, Kaila K J Neurosci 2005;25(22):5280–5289 Spontaneous periodic network events are a characteristic feature of developing neuronal networks, and they are thought to play a crucial role in the maturation of neuronal circuits. In the immature hippocampus, these types of events are seen in intracellular recordings as giant depolarizing potentials (GDPs) during the stage of neuronal development when GABAA-mediated transmission is depolarizing. However, the precise mechanism how GABAergic transmission promotes GDP occurrence is not known. Using whole-cell, cell-attached, perforated-patch, and field-potential recordings in hippocampal slices, we demonstrate here that CA3 pyramidal neurons in the newborn rat generate intrinsic bursts when depolarized. Furthermore, the characteristic rhythmicity of GDP generation is not based on a temporally patterned output of the GABAergic interneuronal network. However, GABAergic depolarization plays a key role in promoting voltage-dependent, intrinsic pyramidal bursting activity. The present data indicate that glutamatergic CA3 neurons have an instructive, pacemaker role in the generation of GDPs, whereas both synaptic and tonic depolarizing GABAergic mechanisms exert a temporally nonpatterned, facilitatory action in the generation of these network events.