ApoE isoform-dependent changes in hippocampal synaptic function

Kimberly M Korwek,Edwin J Weeber,Patrick M Sullivan,Mary Jo Ladu,Justin H Trotter

doi:10.1186/1750-1326-4-21

Abstract

The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR) mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure.

Highlights

More than a decade ago, the allelic variation of apolipoprotein E was associated with an altered risk of Alzheimer's disease (AD) development [1,2]
Unlike reelin-deficient mice, apolipoprotein E (apoE) targeted replacement (TR) and apoEdeficient animals develop normally without gross pathological changes to brain organization suggesting that apoE signaling or apoE isoform expression are not involved in neuronal migration during development
While we hypothesized that the enhanced long-term potentiation (LTP) seen in the presence of apoE4 was related to increased NMDA receptor currents similar to the effect of reelin application, we found that application of either rhapoE2 or rhapoE4 significantly reduced NMDA field potentials from control levels

Summary

Introduction

More than a decade ago, the allelic variation of apolipoprotein E (apoE) was associated with an altered risk of Alzheimer's disease (AD) development [1,2]. The targeted replacement apoE isoform-expressing mice (apoE TR) are a valuable tool for understanding the role of apoE in memory formation and synaptic function These mice express one of the three human apoE isoforms under the control of the endogenous murine promoter [11]. An investigation of a similar line of apoE targeted replacement mice reveals an age-dependent enhancement of CA1 LTP in young apoE4 TR animals compared to wild-type controls [16]. While these data suggest that the actions of apoE isoforms can alter synaptic plasticity, an in-depth study of hippocampus area CA1 synaptic function using all of the available apoE TR mice is absent. We reveal differences in the effects of apoE-isoforms under chronic or acute exposure conditions and explore the possible mechanisms of hippocampal apoE isoform-dependent signaling using both electrophysiological and biochemical techniques

Results

Discussion

Experimental procedures