The Sodium ChannelScn8aIs the Major Contributor to the Postnatal Developmental Increase of Sodium Current Density in Spinal Motoneurons

Abstract

Sodium currents were recorded from motoneurons that were isolated from mice at postnatal days 0-8 (P0-P8) and maintained in culture for 12-24 hr. Motoneurons from normal mice exhibited a more than threefold increase in peak sodium current density from P0 to P8. For mice lacking a functional Scn8a sodium channel gene, motoneuronal sodium current density was comparable at P0 to that of normal mice but failed to increase from P0 to P8. The absence of Scn8a sodium channels is associated with the phenotype "motor end plate disease," which is characterized by a progressive neuromuscular failure and is fatal by 3-4 postnatal weeks. Thus, it appears that the development and function of mature motoneurons depends on the postnatal induction of Scn8a expression.

Sodium Currents in Subthalamic Nucleus Neurons From Nav1.6-Null Mice

“…The simplest interpretation of these results is that the open-channel-blocking mechanism underlying resurgent current can operate with all sodium channel types and is normally more prominent with Na v 1.6 channels, probably because in those channels this mechanism competes more effectively with conventional inactivation (Grieco and Raman 2004), thought to be due to block of channels by the domain III-IV linker (Catterall 2000). Conversely, resurgent current was not detected in some cell types that clearly express Na v 1.6, including CA3 pyramidal neurons and motor neurons (Garcia et al 1998;Pan and Beam 1999;.…”

Postnatal Changes in the Inactivation Properties of Voltage-Gated Sodium Channels Contribute to the Mature Firing Pattern of Spinal Motoneurons

“…This developmental phenomenon has been described in phrenic (Greer and Funk 2005;Martin-Caraballo and Greer 1999), oculomotor (Carrascal et al 2006), hypoglossal (Viana et al 1995), and spinal motoneurons (Fulton and Walton 1986;Vinay et al 2000;Vrbova et al 1985). This ability of motoneurons to discharge action potentials at an increasing rate has been attributed to various factors including an increase in sodium current density (Gao and Ziskind-Conhaim 1998;Garcia et al 1998;McCobb et al 1990), development of repolarizing conductances (McCobb et al 1990;Viana et al 1994;Vinay et al 2000), afterhyperpolarization amplitude increase (Fulton and Walton 1986), the development of calcium channels (McCobb et al 1989;Miles et al 2004;Mynlieff and Beam 1992), or changes in modulatory inputs (reviewed in Kernell 2003;Schmidt and Jordan 2000). In addition to an increase in firing frequency, a second defining characteristic of mature spinal motoneurons is their ability to generate plateau potentials (Perrier and Hounsgaard 2000).…”

“…The sodium channel subtype expression in mammalian spinal cord changes during the early postnatal period as demonstrated by studies examining expression at either the protein (Gordon et al 1987;Schaller and Caldwell 2000) or mRNA level (Beckh et al 1989;Felts et al 1997;Garcia et al 1998;Schaller and Caldwell 2000). Some of these changes have been directly localized to the spinal motoneurons (Schaller and Caldwell 2000) and have been supported by electrophysiological data from mice expressing a spontaneous mutation in a late-developing sodium channel subtype (med mutant; Garcia et al 1998). Taken together, these data suggest that a change in the biophysical characteristics of the sodium channels may, in part, be responsible for the change in firing properties of developing spinal motoneurons.…”

“…Taken together, these data suggest that a change in the biophysical characteristics of the sodium channels may, in part, be responsible for the change in firing properties of developing spinal motoneurons. However, this type of kinetic data is absent from the literature on motoneurons, in all likelihood due to the inherent difficulties associated with voltage-and space-clamping the sodium current in these cells (e.g., Garcia et al 1998).…”

Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels

“…The mammalian Na + channel consists of an = -subunit (approximately 260 kDa) that encodes the core protein of the channel and auxiliary > -subunits (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) that modify the channel function (1). A variety of different isoforms of = -subunits have been identified (2,3).…”