Synaptic NMDA Receptor-Dependent Ca2+ Entry Drives Membrane Potential and Ca2+ Oscillations in Spinal Ventral Horn Neurons

Michael H Alpert,Simon Alford,Alexander G Obukhov

doi:10.1371/journal.pone.0063154

Michael H Alpert, Simon Alford + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0063154

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Journal: PloS one	Publication Date: Apr 30, 2013
Citations: 11	License type: CC BY 4.0

Affiliation: University of Illinois at Chicago

Abstract

During vertebrate locomotion, spinal neurons act as oscillators when initiated by glutamate release from descending systems. Activation of NMDA receptors initiates Ca2+-mediated intrinsic membrane potential oscillations in central pattern generator (CPG) neurons. NMDA receptor-dependent intrinsic oscillations require Ca2+-dependent K+ (KCa2) channels for burst termination. However, the location of Ca2+ entry mediating KCa2 channel activation, and type of Ca2+ channel – which includes NMDA receptors and voltage-gated Ca2+ channels (VGCCs) – remains elusive. NMDA receptor-dependent Ca2+ entry necessitates presynaptic release of glutamate, implying a location at active synapses within dendrites, whereas VGCC-dependent Ca2+ entry is not similarly constrained. Where Ca2+ enters relative to KCa2 channels is crucial to information processing of synaptic inputs necessary to coordinate locomotion. We demonstrate that Ca2+ permeating NMDA receptors is the dominant source of Ca2+ during NMDA-dependent oscillations in lamprey spinal neurons. This Ca2+ entry is synaptically located, NMDA receptor-dependent, and sufficient to activate KCa2 channels at excitatory interneuron synapses onto other CPG neurons. Selective blockade of VGCCs reduces whole-cell Ca2+ entry but leaves membrane potential and Ca2+ oscillations unaffected. Furthermore, repetitive oscillations are prevented by fast, but not slow, Ca2+ chelation. Taken together, these results demonstrate that KCa2 channels are closely located to NMDA receptor-dependent Ca2+ entry. The close spatial relationship between NMDA receptors and KCa2 channels provides an intrinsic mechanism whereby synaptic excitation both excites and subsequently inhibits ventral horn neurons of the spinal motor system. This places the components necessary for oscillation generation, and hence locomotion, at glutamatergic synapses.

Highlights

Throughout the central nervous system oscillatory activity requires the precise temporal activation and inactivation of neurons
We demonstrate that the synaptic coupling of NMDA receptor-dependent Ca2+ entry to KCa2 activation underlies oscillatory properties of ventral horn neurons in the lamprey spinal cord responsible for locomotor pattern generation
Nonlinear membrane properties in response to NMDA receptor activation and Ca2+ entry are central to the generation of membrane potential oscillations in lamprey ventral horn neurons which contribute to the precise rhythmic output of the spinal central pattern generator (CPG)

Summary

Introduction

Throughout the central nervous system oscillatory activity requires the precise temporal activation and inactivation of neurons This may be achieved through intercellular inhibition, and through mechanisms intrinsic to individual neurons. The intrinsic neuronal and synaptic properties that are utilized during oscillatory activity shape the behaviors neurons subserve at the network level. Rhythmic behaviors, such as locomotion, require the transformation of an excitatory command from brainstem neurons into an oscillatory output patterns of motoneuron bursting [1]. KCa2 channels mediate the inactivation of depolarizing drive to an agonist muscle group These channels regulate the frequency and stability of the neural rhythm of the CPG by causing a late afterhyperpolarization following action potentials.

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