TY - JOUR T1 - Presynaptic G-Protein-Coupled Receptors Dynamically Modify Vesicle Fusion, Synaptic Cleft Glutamate Concentrations, and Motor Behavior JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10221 LP - 10233 DO - 10.1523/JNEUROSCI.1404-09.2009 VL - 29 IS - 33 AU - Tatyana Gerachshenko AU - Eric Schwartz AU - Adam Bleckert AU - Huzefa Photowala AU - Andrew Seymour AU - Simon Alford Y1 - 2009/08/19 UR - http://www.jneurosci.org/content/29/33/10221.abstract N2 - Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviors, we investigated effects of presynaptic G-protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gβγ interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that promotes kiss-and-run vesicle fusion. In the lamprey spinal cord, we demonstrate that, although presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion but rather modulates locomotor rhythms. Liberation of presynaptic Gβγ causes substantial inhibition of AMPA receptor-mediated synaptic responses but leaves NMDA receptor-mediated components of neurotransmission mostly intact. Because Gβγ binding to the SNARE complex is displaced by Ca2+-synaptotagmin binding, 5-HT-mediated inhibition displays Ca2+ sensitivity. We show that, as Ca2+ accumulates presynaptically during physiological bouts of activity, 5-HT/Gβγ-mediated presynaptic inhibition is relieved, leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency-dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT G-protein-coupled receptors state-dependently alters vesicle fusion properties to shift the weight of NMDA versus AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behavior. ER -