Maturation of a PKG-dependent retrograde mechanism for exoendocytic coupling of synaptic vesicles

Neuron. 2012 May 10;74(3):517-29. doi: 10.1016/j.neuron.2012.03.028.

Abstract

At presynaptic terminals vesicular membranes are fused into plasma membrane upon exocytosis and retrieved by endocytosis. During a sustained high-frequency transmission, exoendocytic coupling is critical for the maintenance of synaptic transmission. Here, we show that this homeostatic coupling is supported by cGMP-dependent protein kinase (PKG) at the calyx of Held. This mechanism starts to operate after hearing onset during the second postnatal week, when PKG expression becomes upregulated in the brainstem. Pharmacological tests with capacitance measurements revealed that presynaptic PKG activity is supported by a retrograde signal cascade mediated by NO that is released by activation of postsynaptic NMDA receptors. Activation of PKG also upregulates phosphatidylinositol-4,5-bisphosphate, thereby accelerating endocytosis. Furthermore, presynaptic PKG activity upregulates synaptic fidelity during high-frequency transmission. We conclude that maturation of the PKG-dependent retrograde signal cascade strengthens the homeostatic plasticity for the maintenance of high-frequency synaptic transmission at the fast glutamatergic synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Biophysics
  • Brain Stem / cytology
  • Carbazoles / pharmacology
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Cyclic N-Oxides / pharmacology
  • Dose-Response Relationship, Drug
  • Electric Capacitance
  • Electric Stimulation
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Enzyme Inhibitors / pharmacology
  • Exocytosis / physiology
  • Gene Expression Regulation, Developmental / physiology
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Patch-Clamp Techniques
  • Phosphoric Monoester Hydrolases / metabolism
  • Rats
  • Rats, Wistar
  • Synapses / drug effects
  • Synapses / physiology*
  • Synaptic Transmission / physiology
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / physiology*
  • Synaptophysin / metabolism
  • Thionucleotides / pharmacology

Substances

  • Carbazoles
  • Cyclic N-Oxides
  • Enzyme Inhibitors
  • Imidazoles
  • Nerve Tissue Proteins
  • Synaptophysin
  • Thionucleotides
  • KT 5823
  • 8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate
  • 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide
  • Cyclic GMP-Dependent Protein Kinases
  • synaptojanin
  • Phosphoric Monoester Hydrolases
  • Cyclic GMP