[초청강연] Immediate Early Genes and Synaptic Transmission:Protein Synthesis- dependent Synaptic Plasticity and Homeostatic Adaptation

Group I metabotropic glutamate receptor (mGluR1/5) activation induces a form of long-term depression (LTD) that requires rapid de novo protein synthesis. Here, we demonstrate that immediate early gene (IEG) Arc/Arg3.1 and Homer1a regulate synaptic transmission through the dynamic interplay with the mGluR1/5. Rapid translation of Arc facilitates endocytosis of AMPA-type glutamate receptors (AMPARs) and is essential for mGluR-dependent LTD. Arc knock (KO) mice show impairment of mGluR-LTD of the Schaeffer collateral-CA1 synapses, and deletion of Arc prevents mGluR-LTD evident in Fragile X Mental Retardation protein (FMRP) KO mice. The mechanism of mGluR-dependent Arc translation is notable in that it is regulated at the level of elongation rather than initiation, and involves dynamic interactions of mGluR1/5 with eukaryotic elongation factor 2 kinase (eEF2K). eEF2K KO neurons express Arc protein but have a selective deficit in rapid de novo synthesis of Arc, and eEF2K KO mice show a selective deficit of mGluR-LTD. Homer proteins suppress the constitutive activity of mGluR1/5. In Homer triple KO, de-repressed mGluR1/5 reduce surface and synaptic expression of AMPARs and occludes further induction of LTD. Induction of Homer1a, an endogenous dominant negative of long form Homers, by neuronal activity uncovers the constitutive activity of mGluR1/5 and produces homeostatic down-regulation of AMPAR. Furthermore, inhibition of the constitutive activity of mGluR1/5 blocked homeostatic down-regulation of AMPARs caused by chronic activation of network activity. These observations point to an essential role for Arc and Homer1a in mGluR-dependent synaptic plasticity and homeostatic adaptation, and provide a mechanistic basis to understand its’ contribution to diseases of cognition.