title: Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo.
abstract: Homeostatic plasticity mechanisms maintain cellular or network spiking activity within a physiologically functional range through compensatory changes in synaptic strength or intrinsic cellular excitability. Synaptic scaling is one form of homeostatic plasticity that is triggered after blockade of spiking or neurotransmission in which the strengths of all synaptic inputs to a cell are multiplicatively scaled upward or downward in a compensatory fashion. We have shown previously that synaptic upscaling could be triggered in chick embryo spinal motoneurons by complete blockade of spiking or GABAA receptor (GABAAR) activation for 2 d in vivo Here, we alter GABAAR activation in a more physiologically relevant manner by chronically adjusting presynaptic GABA release in vivo using nicotinic modulators or an mGluR2 agonist. Manipulating GABAAR activation in this way triggered scaling in a mechanistically similar manner to scaling induced by complete blockade of GABAARs. Remarkably, we find that altering action-potential (AP)-independent spontaneous release was able to fully account for the observed bidirectional scaling, whereas dramatic changes in spiking activity associated with spontaneous network activity had little effect on quantal amplitude. The reliance of scaling on an AP-independent process challenges the plasticity's relatedness to spiking in the living embryonic spinal network. Our findings have implications for the trigger and function of synaptic scaling and suggest that spontaneous release functions to regulate synaptic strength homeostatically in vivo
  
  
  
  Homeostatic synaptic scaling is thought to prevent inappropriate levels of spiking activity through compensatory adjustments in the strength of synaptic inputs. Therefore, it is thought that perturbations in spike rate trigger scaling. Here, we find that dramatic changes in spiking activity in the embryonic spinal cord have little effect on synaptic scaling; conversely, alterations in GABAA receptor activation due to action-potential-independent GABA vesicle release can trigger scaling. The findings suggest that scaling in the living embryonic spinal cord functions to maintain synaptic strength and challenge the view that scaling acts to regulate spiking activity homeostatically. Finally, the results indicate that fetal exposure to drugs that influence GABA spontaneous release, such as nicotine, could profoundly affect synaptic maturation.
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, Laboratorio de Biomedicina, Facultad de Ciencias de la Vida Escuela Superior Politécnica del Litoral, Guayaquil, Ecuador, and.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Garcia-Bereguiain
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, Doctorado en Ciencias Biológicas Universidad Autónoma de Tlaxcala, Tlaxcala 90062, Mexico.
authors.forename: Carlos
authors.identifier: 0000-0002-3785-4494
authors.initials: C
authors.lastname: Gonzalez-Islas
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Casie
authors.initials: C
authors.lastname: Lindsly
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, pwenner@emory.edu.
authors.forename: Peter
authors.identifier: 0000-0002-7072-2194
authors.initials: P
authors.lastname: Wenner
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002642:Chick Embryo; D002712:Chlorides / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D009068:Movement / Q000187:drug effects; D009415:Nerve Net / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology*; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D000927:Anticonvulsants; D002712:Chlorides; D003521:Cyclopropanes; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D005680:gamma-Aminobutyric Acid; D008012:Lidocaine; D005998:Glycine
keywords: chick embryo; homeostatic plasticity; nicotine; spinal cord; spontaneous release; synaptic scaling