ERG Conductance Expression Modulates the Excitability of Ventral Horn GABAergic Interneurons That Control Rhythmic Oscillations in the Developing Mouse Spinal Cord

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Abstract
During antenatal development, the operation and maturation of mammalian spinal networks strongly depend on the activity of ventral horn GABAergic interneurons that mediate excitation first and inhibition later. Although the functional consequence of GABA actions may depend on maturational processes in target neurons, it is also likely that evolving changes in GABAergic transmission require fine-tuning in GABA release, probably via certain intrinsic mechanisms regulating GABAergic neuron excitability at different embryonic stages. Nevertheless, it has not been possible, to date, to identify certain ionic conductances upregulated or downregulated before birth in such cells. By using an experimental model with either mouse organotypic spinal cultures or isolated spinal cord preparations, the present study examined the role of the ERG current (IK(ERG)), a potassium conductance expressed by developing, GABA-immunoreactive spinal neurons. In organotypic cultures, only ventral interneurons with fast adaptation and GABA immunoreactivity, and only after 1 week in culture, were transformed into high-frequency bursters by E4031, a selective inhibitor ofIK(ERG)that also prolonged and made more regular spontaneous bursts. In the isolated spinal cord in which GABA immunoreactivity andm-ergmRNA were colocalized in interneurons, ventral root rhythms evoked by NMDA plus 5-hydroxytryptamine were stabilized and synchronized by E4031. All of these effects were lost after 2 weeks in culture or before birth in coincidence with decreasedm-ergexpression. These data suggest that, during an early stage of spinal cord development, the excitability of GABAergic ventral interneurons important for circuit maturation depended, at least in part, on the function ofIK(ERG).