Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APC(Cdh1) interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC(Cdh1)-dependent degradation pathway.
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http://dx.doi.org/10.1038/nn.2715 | DOI Listing |
Sleep
January 2025
Chronobiology and Sleep Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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January 2025
Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel.
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View Article and Find Full Text PDFNat Cell Biol
January 2025
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
Plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration.
View Article and Find Full Text PDFPLoS Comput Biol
January 2025
Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands.
Although the primary function of excitatory-inhibitory (E-I) homeostasis is the maintenance of mean firing rates, the conjugation of multiple homeostatic mechanisms is thought to be pivotal to ensuring edge-of-bifurcation dynamics in cortical circuits. However, computational studies on E-I homeostasis have focused solely on the plasticity of inhibition, neglecting the impact of different modes of E-I homeostasis on cortical dynamics. Therefore, we investigate how the diverse mechanisms of E-I homeostasis employed by cortical networks shape oscillations and edge-of-bifurcation dynamics.
View Article and Find Full Text PDFSci Rep
December 2024
Department of Nephrology, CHU Lille, University of Lille, Lille, 59000, France.
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