Endogenous release of 5-HT modulates the plateau phase of NMDA-induced membrane potential oscillations in lamprey spinal neurons

Abstract

The lamprey central nervous system has been used extensively as a model system for investigating the networks underlying vertebrate motor behavior. The locomotor networks can be activated by application of glutamate agonists, such as N-methyl-D-aspartic acid (NMDA), to the isolated spinal cord preparation. Many spinal neurons are capable of generating pacemaker-like membrane potential oscillations upon activation of NMDA receptors. These oscillations rely on the voltage-dependent properties of NMDA receptors in interaction with voltage-dependent potassium and calcium-dependent potassium (K(Ca)) channels, as well as low voltage-activated calcium channels. Upon membrane depolarization, influx of calcium will activate K(Ca) channels, which in turn, will contribute to repolarization and termination of the depolarized phase. The appearance of the NMDA-induced oscillations varies markedly between spinal cord preparations; they may either have a pronounced, depolarized plateau phase or be characterized by a short-lasting depolarization lasting approximately 200-300 ms without a plateau. Both types of oscillations increase in frequency with increased concentrations of NMDA. Here, we characterize these two types of membrane potential oscillations and show that they depend on the level of endogenous release of 5-HT in the spinal cord preparations. In the lamprey, 5-HT acts to block voltage-dependent calcium channels and will thereby modulate the activity of K(Ca) channels. When 5-HT antagonists were administered, the plateau-like oscillations were converted to the second type of oscillations lacking a plateau phase. Conversely, plateau-like oscillations can be induced or prolonged by 5-HT agonists. These properties are most likely of significance for the modulatory action of 5-HT on the spinal networks for locomotion.

Modulation of NMDA-mediated intrinsic membrane properties of ascending commissural interneurons in neonatal rat spinal cord

“…Another important character-istic of aCINs is NMDA-induced membrane oscillation. This is an essential property for facilitation of locomotion and has been demonstrated in rodents (Hochman et al, 1994;Schmidt et al, 1998) and other species (Wang et al, 2014). Interestingly, similar membrane oscillations have been reported for aCINs modulated by 5-HT and ACh in rodents (Carlin et al, 2006).…”

Visualization of the relative contributions of conductances in neuronal models with similar behavior and different conductance densities

“…The beginning of this curve corresponds to a high frequency oscillation that occurs after spike termination. This type of activity is termed plateau oscillations and was reported in models of leech heart interneurons (Cymbalyuk and Calabrese, 2000) and in experiments in lamprey spinal neurons (Wang et al, 2014). These features are hardly visible in the traces in Fig.…”

Sensory Activation of Command Cells for Locomotion and Modulatory Mechanisms: Lessons from Lampreys

“…The oscillations require Ca 2+ permeation of the NMDA receptors and subsequent activation of a KCa2 channel. The prolongation of the depolarizing phase of these oscillations caused by 5-HT may be mediated by direct interaction of 5-HT receptors on KCa2 channels, or alternatively, via an indirect inhibition of N-methyl-D-aspartate receptors (NMDARs; Schotland and Grillner, 1993 ) or voltage-gated calcium channels (VGCCs; Wang et al, 2014 ) supplying Ca 2+ for KCa2 channels responsible for the repolarization. More recent work ties the activation of NMDA receptors and Ca 2+ permeation of these receptors directly to the activation of KCa2 channels, which are held in very close proximity (Alpert and Alford, 2013 ; Nanou et al, 2013 ).…”