Early life stress amplifies fear responses and hippocampal synaptic potentiation in the APPswe/PS1dE9 Alzheimer mouse model

Abstract

Cognitive deficits and alterations in emotional behaviour are typical features of Alzheimer's disease (AD). Moreover, exposure to stress or adversity during the early life period has been associated with an acceleration of cognitive deficits and increased AD pathology in transgenic AD mouse models. Whether and how early life adversity affects fear memory in AD mice remains elusive.We therefore investigated whether exposure to early life stress (ELS) alters fear learning in APPswe/PS1dE9 mice, a classic mouse model for AD, and whether this is accompanied by alterations in hippocampal synaptic potentiation, an important cellular substrate for learning and memory.Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing the dams and her pups with limited nesting and bedding material from postnatal days 2–9. Following a fear conditioning paradigm, 12-month-old ELS-exposed APPswe/PS1dE9 mice displayed enhanced contextual freezing behaviour, both in the conditioning context and in a novel context. ELS-exposed APPswe/PS1dE9 mice also displayed enhanced hippocampal synaptic potentiation, even in the presence of the GluN2B antagonist Ro25–6981 (which prevented synaptic potentiation in control mice). No differences in the level of PSD-95 or synaptophysin were observed between the groups.We conclude that in APPswe/PS1dE9 mice, ELS increases fear memory in the conditioning context as well as a novel context, which is accompanied by aberrant hippocampal synaptic potentiation. These results may help to understand how individual differences in the vulnerability to develop AD arise and emphasise the importance of the early postnatal time window in these differences.This article is part of Special Issue entitled: Lifestyle and Brain Metaplasticity.