University of Illinois at Chicago
journal.pone.0063154.pdf (7.96 MB)

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

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journal contribution
posted on 2015-08-13, 00:00 authored by Michael H. Alpert, Simon Alford
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+ (K(Ca)2) channels for burst termination. However, the location of Ca2+ entry mediating K(Ca)2 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 K(Ca)2 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 K(Ca)2 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 K(Ca)2 channels are closely located to NMDA receptor-dependent Ca2+ entry. The close spatial relationship between NMDA receptors and K(Ca)2 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.


National Institutes of Health Grant RO1 MH 084874;


Publisher Statement

© 2013 Alpert, Alford. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PLoS One


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