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

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 (I K(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 of I K(ERG) that also prolonged and made more regular spontaneous bursts. In the isolated spinal cord in which GABA immunoreactivity and m-erg mRNA 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 decreased m-erg expression. 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 of I K(ERG) .

Developmental Tuning and Decay in Senescence of Oscillations Linking the Corticospinal System

“…Indeed, while there was no correlation between the absolute power in each frequency between EEG and EMG, we found a significant correlation between the ratio of the power in lower and higher frequencies in the SMC-EEG and the same ratio in the relative power of the ROP-EMG. However, the capacity for spinal motoneuronal pools to oscillate at higher frequencies is also dependent upon fast synaptic inhibition and developmental changes in the pattern of spinal inhibition will also influence their intrinsic oscillatory activity and may account, at least in part, for the frequency shift (O'Sullivan et al, 1991;Mc Donough et al, 2001;Furlan et al, 2007;Sibilla and Ballerini, 2009). …”

“…Intracortical inhibition is not mature until adulthood and is reduced in the elderly (Peinemann et al, 2001;Mall et al, 2004;Walther et al, 2009). The morphological properties of alpha-motoneurons and their excitatory and inhibitory control mature during development and are altered in the elderly (O'Sullivan et al, 1991;Erim et al, 1999;Mc Donough et al, 2001;Mentis et al, 2002;Furlan et al, 2007;Carlin et al, 2008;Sibilla and Ballerini, 2009). Finally, both the diameter and excitability of corticospinal axons increase during adolescence Müller and Hömberg, 1992) while white matter hyperintensities within the corticospinal tract become prevalent in old age (Moscufo et al, 2009).…”

Homeostatic Control of Sensory Output in Basal Vomeronasal Neurons: Activity-Dependent Expression ofEther-à-Go-Go-Related Gene Potassium Channels

“…) were identified and studied with a standard high [K ϩ ] o extracellular solution (S 3 ; calculated Nernst equilibrium potential for K ϩ , Ϫ32.5 mV) (Sacco et al, 2003;Furlan et al, 2007;Hirdes et al, 2005),…”

“…However, gating properties vary substantially between endogenous and heterologously expressed ERG channels and between subunits (Pond and Nerbonne, 2001;Hirdes et al, 2005). So far, neuronal ERG currents have been described in cerebellar Purkinje neurons (Sacco et al, 2003) and ventral horn interneurons (Furlan et al, 2007).…”

Effects of Ranolazine, a Novel Anti-anginal Drug, on Ion Currents and Membrane Potential in Pituitary Tumor GH3 Cells and NG108-15 Neuronal Cells

“…Previous reports showed the ability of risperidone or ceramide to suppress I K(IR) in pituitary GH 3 cells (14,15). Pharmacological blockade of this current in the CNS has been recently noted to result in changes in neuronal excitability that would alter synaptic integration (16,17). Alternatively, several studies reported that ranolazine can block the human ether-à-go-go-related gene (HERG) K + current expressed in Xenopus oocytes and in HEK293 cells (18,19).…”