ApoE isoform-dependent deficits in extinction of contextual fear conditioning

R. H.J. Olsen, M. Agam, M. J. Davis, J. Raber

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

ApoE2 mice show acquisition and retrieval of conditioned fear but in contrast to apoE3 and apE4 mice no extinction. The three major human apoE isoforms (apoE2, apoE3 and apoE4) are encoded by distinct alleles (ε{lunate}2, ε{lunate}3 and ε{lunate}4). Compared with ε{lunate}3, ε{lunate}4 is associated with increased risk to develop Alzheimer's disease (AD), cognitive impairments in Parkinson's disease (PD), and other conditions. In contrast, a recent study indicated an increased susceptibility to the recurring and re-experiencing symptom cluster of Post-Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ε{lunate}2 allele. Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster. In this study, acquisition (day 1, training), consolidation (day 2, first day of re-exposure) and extinction (days 2-5) of conditioned contextual fear in human apoE2, apoE3 and apoE4 targeted replacement and C57BL/6J wild-type (WT) mice was investigated. Male and female apoE2 showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction. In contrast, WT, apoE3 and apoE4 mice showed extinction. While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction. Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals. These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear.

Original languageEnglish (US)
Pages (from-to)806-812
Number of pages7
JournalGenes, Brain and Behavior
Volume11
Issue number7
DOIs
StatePublished - Oct 1 2012

Keywords

  • Acquisition
  • Extinction
  • PTSD
  • apoE

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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