ApoE Receptor 2 Regulates Synapse and Dendritic Spine Formation

Sonya B Dumanis,Hyang-Sook Hoe,Hyun-Jung Cha,Ji-Yun Lee,Justin H Trotter,Matthew Spitzer,R Scott Turner,Jung Min Song,Daniel T S Pak,G William Rebeck,Edwin J Weeber,Mark Baccei

doi:10.1371/journal.pone.0017203

Sonya B Dumanis, Hyang-Sook Hoe + Show 10 more

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https://doi.org/10.1371/journal.pone.0017203

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Abstract

BackgroundApolipoprotein E receptor 2 (ApoEr2) is a postsynaptic protein involved in long-term potentiation (LTP), learning, and memory through unknown mechanisms. We examined the biological effects of ApoEr2 on synapse and dendritic spine formation—processes critical for learning and memory.Methodology/Principal FindingsIn a heterologous co-culture synapse assay, overexpression of ApoEr2 in COS7 cells significantly increased colocalization with synaptophysin in primary hippocampal neurons, suggesting that ApoEr2 promotes interaction with presynaptic structures. In primary neuronal cultures, overexpression of ApoEr2 increased dendritic spine density. Consistent with our in vitro findings, ApoEr2 knockout mice had decreased dendritic spine density in cortical layers II/III at 1 month of age. We also tested whether the interaction between ApoEr2 and its cytoplasmic adaptor proteins, specifically X11α and PSD-95, affected synapse and dendritic spine formation. X11α decreased cell surface levels of ApoEr2 along with synapse and dendritic spine density. In contrast, PSD-95 increased cell surface levels of ApoEr2 as well as synapse and dendritic spine density.Conclusions/SignificanceThese results suggest that ApoEr2 plays important roles in structure and function of CNS synapses and dendritic spines, and that these roles are modulated by cytoplasmic adaptor proteins X11α and PSD-95.

Highlights

ApoE receptors are a family of transmembrane proteins that mediate endocytosis of ligands and are recycled back to the cell surface [1]
To determine whether Apolipoprotein E receptor 2 (ApoEr2) is expressed at the synapse, primary hippocampal neurons were immunostained with anti-ApoEr2 and anti-PSD-95 antibodies (Fig. 1A)
ApoEr2 immunoreactivity was highest in pyramidal neurons, where it was found to have a punctate distribution throughout dendritic processes, and where it co-localized with the postsynaptic marker PSD-95, suggesting that ApoEr2 is present in synapses (Fig. 1A)

Summary

Introduction

ApoE receptors are a family of transmembrane proteins that mediate endocytosis of ligands and are recycled back to the cell surface [1]. ApoE receptors include the LDL receptor, LDL receptor related proteins (LRP-1, LRP-1B, LRP-2), ApoE receptor 2 (ApoEr2), and the very low density lipoprotein receptor (VLDLr) Each of these type I transmembrane receptors has a large N-terminal extracellular domain, with multiple ligandbinding repeats, and small C-terminal cytoplasmic adaptor domains with one or several NPXY sequences for receptormediated endocytosis. ApoEr2 interacts with PSD-95 [5,6,7,8], a major postsynaptic density protein important for synapse formation and function [9], through a domain encoded by the alternatively spliced ApoEr2 exon 19 [10] This region of ApoEr2 regulates memory and behavior in mice [5]. We examined the biological effects of ApoEr2 on synapse and dendritic spine formation—processes critical for learning and memory

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