Similar Properties of Transient, Persistent, and Resurgent Na Currents in GABAergic and non-GABAergic MVN neurons

Sodium currents in fast firing neurons are tuned to support sustained firing rates > 50-60 Hz. This is typically accomplished with fast channel kinetics and the ability to minimize the accumulation of Na channels into inactivated states. Neurons in the medial vestibular nuclei (MVN) can fire at exceptionally high rates, but their Na currents have never been characterized. In this study, Na current kinetics and voltage dependent properties were compared in two classes of MVN neurons with distinct firing properties. Non-GABAergic neurons (fluorescently labeled in YFP-16 transgenic mice) have action potentials with faster rise and fall kinetics and sustain higher firing rates than GABAergic neurons (fluorescently labeled in GIN transgenic mice). A previous study showed that these neurons express a differential balance of K currents. To determine whether the Na currents in these two populations were different, their kinetics and voltage dependent properties were measured in acutely dissociated neurons from 24 40 day-old mice. All neurons expressed persistent Na currents and large transient Na currents with resurgent kinetics tuned for fast firing. No differences were found between the Na currents expressed in GABAergic and non-GABAergic MVN neurons, suggesting that differences in properties of these neurons are tuned by their K currents. Page 1 of 24 Articles in PresS. J Neurophysiol (February 20, 2008). doi:10.1152/jn.01389.2007 Copyright © 2008 by the American Physiological Society. 2 Introduction Different firing properties of neurons are established by the tuning of ionic currents, apparent at the molecular level in the diversity of potassium (K) channel and sodium (Na) channel expression across cell types (Catterall et al. 2005; Coetzee et al. 1999). Historically, the kinetic properties of voltage-gated Na channels were considered to be relatively homogeneous, but more recently, important differences in their kinetic and voltage dependent properties have been identified across cell types with different firing properties (reviewed in Bean 2007). For example, Na currents in regular spiking hippocampal neurons have different inactivation kinetics and voltage dependences than Na currents in fast firing interneurons in the hippocampus (Martina and Jonas 1997) and Purkinje cells in the cerebellum (Raman and Bean 1997). During firing, Na current availability is limited by the accumulation of Na channels into fast (Armstrong 1981; Stuhmer et al. 1989; Vassilev et al. 1988) and slow inactivated states (Mitrovic et al. 2000; Ong et al. 2000; Ulbricht 2005). Na currents in fast firing neurons are slower to enter and faster to recover from these inactivated states than Na currents in slower firing neurons (Martina and Jonas 1997). Additionally, Na currents in many fast firing neurons are protected from inactivation by an endogenous blocking particle that competes for position in a Na channel pore with the channel’s inactivation gate (Grieco et al. 2005; Raman and Bean 1997). This mechanism is revealed in voltage clamp experiments by the presence of a resurgent Na current (Afshari et al. 2004; Aman and Raman 2007; Baufreton et al. 2005; Do and Bean 2003; Raman and Bean 1997; Raman et al. 2000). Page 2 of 24