Platelet-derived Growth Factor-mediated Induction of the Synaptic Plasticity Gene Arc/Arg3.1

Fuwang Peng,Honghong Yao,Xuetao Bai,Xuhui Zhu,Benjamin C Reiner,Michael Beazely,Keiko Funa,Huangui Xiong,Shilpa Buch

doi:10.1074/jbc.m110.107003

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.

Highlights

Polypeptide chains (A-D) that can form homo- or heterodimers (PDGF-AA, -BB, -AB, -CC, and -DD) and can bind two types of receptors (PDGF-␣ and -␤ receptor) [2]
Platelet-derived growth factor (PDGF) Induces Arc Expression in Neurons—Because the expression of Arc/Arg3.1 gene is implicated in synapse plasticity and long term potentiation, we first wanted to investigate the effects of PDGF on Arc expression in primary rat hip
STI-571 followed by PDGF, and 3 h later the animals were perfused and decapitated

Summary

Introduction

Polypeptide chains (A-D) that can form homo- or heterodimers (PDGF-AA, -BB, -AB, -CC, and -DD) and can bind two types of receptors (PDGF-␣ and -␤ receptor) [2]. Pretreatment of hippocampal neurons with the receptor-tyrosine kinase inhibitor STI-571 (1 ␮M) for 1 h resulted in abrogation of PDGF-induced Arc expression (Fig. 1C), underscoring the role of PDGF receptortyrosine kinase in this process. To elucidate the roles of MAPK/ERK and PI3K pathways in PDGF-mediated Arc expression, we pretreated rat hippocampal neurons with either the PI3K inhibitor LY294002 (10 ␮M) or the MEK inhibitor U0126 (20 ␮M) for 1 h before exposing the neurons to PDGF for 30 min.

Results

Conclusion