Mechanisms of Synaptic Depression: Focus on Rap Signaling Pathways

Summary

Principal Investigator: J Julius Zhu
Abstract: Long-term synaptic depression (LTD) and depotentiation, the two forms of sustained synaptic depression after periods of repetitive synaptic activity, are extensively studied examples of vertebrate synaptic plasticity. The cellular and molecular mechanisms responsible for LTD and depotentiation will likely elucidate physiological and pathological phenomena of neural development, adaptation, learning and memory. There is now compelling evidence that repetitive synaptic activity leads to activation of NMDA- sensitive glutamate receptors (NMDA-Rs) and removal of postsynaptic AMPA-sensitive glutamate receptors (AMPA-Rs) from excitatory synapses during LTD and depotentiation. However, the biochemical pathways that link NMDA-R activity to AMPA-R trafficking are largely unknown. We have previously reported that small GTPase Rapl controls LTD via activation of p38MAPK. In a preliminary study, we observed that small GTPase Rap2 controls depotentiation via activation of JNK. Based on these findings, I proposed a new model that Rapl and Rap2 signal synaptic depression via two independent signaling pathways. We will test three hypotheses in this model with three aims, respectively, using an organotypic culture hippocampal slice preparation. This preparation allows us to manipulate synaptic activity and signaling molecules'activity using physiology, pharmacology and recombinant protein delivery methods. We will assay the effects of these manipulations by examining electrophysiologically tagged recombinant AMPA-R-mediated currents, measuring synaptic responses in GluRl and GluR2 knockout mice, as well as quantifying phosphorylated or active endogenous signaling molecules and glutamate receptors. Combining these approaches, we will determine whether: (Aim 1) Rapl-p38MAPK signals LTD whereas Rap2-JNK signals depotentiation;(Aim 2) different downstream signaling molecules relay Rapl-p38MAPK and Rap2-JNK pathways;and (Aim 3) different upstream signaling molecules control Rapl-p38MAPK and Rap2-JNK pathways. Because genetic defects in signaling molecules or enzymes controlling Rap signaling pathways lead to severe mental retardation, the findings from this study should also suggest additional molecular targets for novel genetic and pharmacological strategies that may efficaciously treat these insidious mental diseases.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Synaptic AMPA receptor exchange maintains bidirectional plasticity
    Stefanie G McCormack
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    Neuron 50:75-88. 2006
  2. pmc Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome
    Hailan Hu
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    J Neurosci 28:7847-62. 2008
  3. pmc Epac signaling is required for hippocampus-dependent memory retrieval
    Ming Ouyang
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Proc Natl Acad Sci U S A 105:11993-7. 2008
  4. pmc Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools
    Anders Kielland
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    Neuron 62:84-101. 2009
  5. pmc Activity level-dependent synapse-specific AMPA receptor trafficking regulates transmission kinetics
    J Julius Zhu
    Departments of Pharmacology and Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    J Neurosci 29:6320-35. 2009
  6. pmc Ras and Rap signaling in synaptic plasticity and mental disorders
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
    Neuroscientist 17:54-78. 2011

Scientific Experts

  • J Julius Zhu
  • Ruth L Stornetta
  • Anders Kielland
  • Genrieta Bochorishvili
  • Lei Zhang
  • Hailan Hu
  • Ming Ouyang
  • Stefanie G McCormack
  • Diane L Rosin
  • Paul Heggelund
  • James Corson
  • Steven A Thomas
  • Linda Van Aelst
  • Yinghua Zhu
  • Frank Schwede
  • Yi Qin

Detail Information

Publications6

  1. ncbi Synaptic AMPA receptor exchange maintains bidirectional plasticity
    Stefanie G McCormack
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    Neuron 50:75-88. 2006
    ..These results suggest that the previously hypothesized "slot" proteins, rather than AMPA-Rs, code and maintain transmission efficacy at central synapses...
  2. pmc Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome
    Hailan Hu
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    J Neurosci 28:7847-62. 2008
    ..These results suggest aberrant Ras signaling as a novel mechanism for fragile X syndrome and indicate manipulating Ras-PI3K-PKB signaling to be a potentially effective approach for treating patients with fragile X syndrome...
  3. pmc Epac signaling is required for hippocampus-dependent memory retrieval
    Ming Ouyang
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 6084, USA
    Proc Natl Acad Sci U S A 105:11993-7. 2008
    ..These findings demonstrate that cAMP signaling through Epac (as well as PKA) plays an essential role in cognition...
  4. pmc Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools
    Anders Kielland
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    Neuron 62:84-101. 2009
    ....
  5. pmc Activity level-dependent synapse-specific AMPA receptor trafficking regulates transmission kinetics
    J Julius Zhu
    Departments of Pharmacology and Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    J Neurosci 29:6320-35. 2009
    ..Thus, synapse-specific AMPA-R trafficking coarsely sets and synaptic activity finely tunes transmission kinetics and integration properties at different synapses in central neurons...
  6. pmc Ras and Rap signaling in synaptic plasticity and mental disorders
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
    Neuroscientist 17:54-78. 2011
    ..Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases...