The kinase activity of EphA4 mediates homeostatic scaling-down of synaptic strength via activation of Cdk5

Neurons within a network have the ability to homeostatically scale-down their excitatory synaptic strength under conditions of persistent neuronal activity elevation, a process pivotal to neural circuit stability. How this homeostatic regulation is achieved at the molecular level in developing neura...

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Bibliographic Details
Published in:Neuropharmacology 2013-02, Vol.65, p.232-243
Main Authors: Peng, Yi-Rong, Hou, Zai-Hua, Yu, Xiang
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Cdk5
Cell culture
Cells, Cultured
Cyclin-Dependent Kinase 5 - metabolism
Cyclin-Dependent Kinase 5 - physiology
Enzyme Activation - physiology
EphA4
Excitatory Postsynaptic Potentials - physiology
HEK293 Cells
Homeostasis - physiology
Homeostatic plasticity
Humans
Neuronal activity
Rats
Rats, Sprague-Dawley
Receptor, EphA4 - metabolism
Receptor, EphA4 - physiology
Synapses - enzymology
Synaptic scaling
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Summary:Neurons within a network have the ability to homeostatically scale-down their excitatory synaptic strength under conditions of persistent neuronal activity elevation, a process pivotal to neural circuit stability. How this homeostatic regulation is achieved at the molecular level in developing neural circuits, which face gradually elevated neuronal activity as part of circuit wiring, is not well-understood. Using dissociated hippocampal neuronal cultures, we identified a critical and cell autonomous role for the receptor tyrosine kinase EphA4 in mediating activity-induced homeostatic down-regulation of excitatory synaptic strength. Reducing the endogenous level of EphA4 in individual neurons by RNAi effectively blocked activity-induced scaling-down of excitatory synaptic strength, while co-transfection of RNAi resistant EphA4 rescued this effect. Furthermore, interfering with EphA4 forward signaling using EphA4-Fc blocked activity-induced homeostatic synaptic scaling-down, while direct activation of EphA4 with its ligand EphrinA1 weakened excitatory synaptic strength. Up- or down-regulating EphA4 function in individual neurons also did not affect the density of excitatory synapses. The kinase activities of EphA4 and its downstream effector Cdk5 were both required for homeostatic synaptic scaling, as overexpression of EphA4 with constitutively active kinase activity reduced excitatory synaptic strength, while interfering with either the kinase activity of EphA4 or Cdk5 blocked activity-induced synaptic scaling. Consistently, the activities of EphA4 and Cdk5 increased significantly during global and persistent activity elevation. Together, our work demonstrated that the kinase activity of EphA4, via activation of downstream Cdk5 activity, mediates the scaling-down of excitatory synaptic strength under conditions of global activity elevation. ► EphA4 mediates activity-induced homeostatic down-regulation of mEPSCs. ► The kinase activity of EphA4 is necessary and sufficient for mEPSC scaling-down. ► The kinase activity of Cdk5, a downstream effector of EphA4, is also required. ► The activities of EphA4 and Cdk5 significantly increased during activity elevation. ► EphA4 protein level is eventually down-regulated, together with GluR1 and GluR2.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2012.10.012