Platelet-derived growth factor-mediated induction of the synaptic plasticity gene Arc/Arg3.1.

Abstract

Platelet-derived growth factor (PDGF) is a pleiotropic protein with critical roles in both developmental as well as pathogenic processes. In the central nervous system specifically, PDGF is critical for neuronal proliferation and differentiation and has also been implicated as a neuroprotective agent. Whether PDGF also plays a role in synaptic plasticity, however, remains poorly understood. In the present study we demonstrated that in the rat hippocampal neurons PDGF regulated the expression of Arc/Arg3.1 gene that has been implicated in both synapse plasticity and long term potentiation. Relevance of these findings was further confirmed in vivo by injecting mice with intracerebral inoculations of PDGF, which resulted in a rapid induction of Arc in the hippocampus of the injected mice. PDGF induced long term potentiation in rat hippocampal slices, which was abolished by PDGF receptor-tyrosine kinase inhibitor STI-571. We also present evidence that PDGF-mediated induction of Arc/Arg3.1 involved activation of the MAPK/ERK (MEK) pathway. Additionally, induction of Arc/Arg3.1 also involved the upstream release of intracellular calcium stores, an effect that could be blocked by thapsigargin but not by EGTA. Pharmacological approach using inhibitors specific for either MAPK/ERK phosphorylation or calcium release demonstrated that the two pathways converged downstream at a common point involving activation of the immediate early gene Egr-1. Chromatin immunoprecipitation assays demonstrated the binding of Egr-1, but not Egr-3, to the Arc promoter. These findings for the first time, thus, suggest an additional role of PDGF, that of induction of Arc.

• Authors: Fuwang Peng, Honghong Yao, Xuetao Bai, Xuhui Zhu, Benjamin C Reiner, Michael Beazely, Keiko Funa, Huangui Xiong, Shilpa Buch
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 28 Pg. 21615-24 (Jul 09 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20452974 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytoskeletal Proteins
• Nerve Growth Factors
• Nerve Tissue Proteins
• Platelet-Derived Growth Factor
• activity regulated cytoskeletal-associated protein
• Phosphatidylinositol 3-Kinases
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cell Proliferation
• Cytoskeletal Proteins (metabolism)
• Electrophysiology
• Enzyme Activation
• Female
• Gene Expression Regulation
• Hippocampus (metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Inbred C57BL
• Nerve Growth Factors (metabolism)
• Nerve Tissue Proteins (metabolism)
• Phosphatidylinositol 3-Kinases
• Platelet-Derived Growth Factor (metabolism)
• Rats
• Rats, Sprague-Dawley