Contribution of Persistent Sodium Current to Locomotor Pattern Generation in Neonatal Rats

Abstract

The persistent sodium current (I(NaP)) is known to play a role in rhythm generation in different systems. Here, we investigated its contribution to locomotor pattern generation in the neonatal rat spinal cord. The locomotor network is mainly located in the ventromedial gray matter of upper lumbar segments. By means of whole cell recordings in slices, we characterized membrane and I(NaP) biophysical properties of interneurons located in this area. Compared with motoneurons, interneurons were more excitable, because of higher input resistance and membrane time constant, and displayed lower firing frequency arising from broader spikes and longer AHPs. Ramp voltage-clamp protocols revealed a riluzole- or TTX-sensitive inward current, presumably I(NaP), three times smaller in interneurons than in motoneurons. However, in contrast to motoneurons, I(NaP) mediated a prolonged plateau potential in interneurons after reducing K(+) and Ca(2+) currents. We further used in vitro isolated spinal cord preparations to investigate the contribution of I(NaP) to locomotor pattern. Application of riluzole (10 muM) to the whole spinal cord or to the upper lumbar segments disturbed fictive locomotion, whereas application of riluzole over the caudal lumbar segments had no effect. The effects of riluzole appeared to arise from a specific blockade of I(NaP) because action potential waveform, dorsal root-evoked potentials, and miniature excitatory postsynaptic currents were not affected. This study provides new functional features of ventromedial interneurons, with the first description of I(NaP)-mediated plateau potentials, and new insights into the operation of the locomotor network with a critical implication of I(NaP) in stabilizing the locomotor pattern.

The Persistent Sodium Current Generates Pacemaker Activities in the Central Pattern Generator for Locomotion and Regulates the Locomotor Rhythm

“…This protocol enables to both abolish synaptic transmission and prevent bursting properties that rely on Ca 2ϩ -dependent mechanisms. As demonstrated in our previous study (Tazerart et al 2007b) ] o . A2, Repetitive events recordedinthecell-attachedconfigurationfromthesurfaceofaburstingventromedialinterneuron.A3,Slowafterhyperpolarizationsafter a spike (truncated) evoked bya3mscurrent pulse (bottom trace) before (black trace) and after removing [Ca 2ϩ ] o (gray trace).…”

“…If pacemaker neurons are assumed to be important in the operation of mammalian locomotor CPG (Rybak et al, 2006;McCrea and Rybak, 2007), then I NaPdependent bursting properties should exist in the spinal cord. The widespread expression of the I NaP in the locomotor CPG region (Tazerart et al, 2007b;Theiss et al, 2007), and particularly in commissural interneurons (Zhong et al, 2007) critical for leftright coordination of locomotor movements (Butt and Kiehn, 2003), supports this hypothesis.…”

“…This spinal region contains conditional pacemaker cells characterized by intrinsic bursting properties that are induced by activating NMDA receptors and independent of sodium currents (Hochman et al, 1994;Wilson et al, 2005). Although hypothesized to be involved in rhythmogenesis (Schmidt et al, 1998), these sodium-independent bursting properties are not sufficient by themselves to generate the locomotor rhythm because a specific blockade of the persistent sodium current (I NaP ) abolishes fictive locomotion (Tazerart et al, 2007b;Zhong et al, 2007) and furthermore mostly depresses the disinhibited locomotor-like rhythm (Darbon et al, 2004;Taccola and Nistri, 2007). I NaP is ubiquitously associated with pacemaker properties in a variety of supraspinal neuronal populations (Thoby-Brisson and Ramirez, 2001;Del Negro et al, 2005;Brocard et al, 2006;van Drongelen et al, 2006).…”

Firing and Cellular Properties of V2a Interneurons in the Rodent Spinal Cord

“…7D). PICs were present in most cells tested (53 of 71) but were much smaller (mean peak current, 11 Ϯ 1 pA) than what has been reported in other ventrally located cells (Tazerart et al, 2007(Tazerart et al, , 2008Theiss et al, 2007;Zhong et al, 2007;Ziskind-Conhaim et al, 2008). However, our experiments were performed in the absence of any potassium channel blockers, and therefore active potassium con- Figure 6.…”

Une nouvelle cible thérapeutique dans le traitement de la spasticité après une lésion de la moelle épinière : la calpaïne

“…Cette propriété, intrinsèque au motoneurone, se manifeste par l'émission continue de potentiels d'action à la suite d'une brève dépolarisation (Figure 3a et 3b). Nous avions démontré antérieurement que le courant sodique persistant (I NaP ), largement exprimé au sein du réseau locomoteur [23][24][25][26], est essentiel dans cette décharge en plateau [22]. Ce courant augmente considérablement à la suite d'une lésion de la moelle épinière (Figure 3c) et contribue à l'hyperexcitabilité motoneuronale en favorisant l'émer-gence des potentiels de plateau de très longue durée [27] (Figure 3d).…”