title: Synaptic NMDA receptor-dependent Ca²⁺ entry drives membrane potential and Ca²⁺ oscillations in spinal ventral horn neurons.
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⁺ (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.
authors: Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Michael H
authors: MH
authors: Alpert
authors: Simon
authors: S
authors: Alford
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007798:Lampreys; D008564:Membrane Potentials / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D004533:Egtazic Acid; D016202:N-Methylaspartate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
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