A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1

MRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, UK.
Molecular Brain (Impact Factor: 4.9). 07/2010; 3(1):21. DOI: 10.1186/1756-6606-3-21
Source: PubMed


Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Abeta are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region.

Download full-text


Available from: Robin Morton
  • Source
    • "In contrast with studies of the SCCP in Aβ overproducing mice, including those performed in our laboratory [22-25], input-output properties of MF responses were not dependent on genotype (Figure 1A). In contrast, both short term synaptic plasticity and LTP in the MFP were modified in the Aβ peptide over-producing mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aβ peptides derived from the cleavage of amyloid precursor protein are widely believed to play an important role in the pathophysiology of Alzheimer's disease. A common way to study the impact of these molecules on CNS function is to compare the physiology of transgenic mice that overproduce Aβ with non-transgenic animals. In the hippocampus, this approach has been frequently applied to the investigation of synaptic transmission and plasticity in the perforant and Schaffer collateral commissural pathways, the first and third components of the classical hippocampal trisynaptic circuit, respectively. Similar studies however have not been carried out on the remaining component of the trisynaptic circuit, the mossy fibre pathway. Using transverse hippocampal slices prepared from ~2 year old animals we have compared mossy fibre synaptic function in wild-type mice and their Tg2576 littermates which age-dependently overproduce Aβ. Input-output curves were not altered in slices from Tg2576 mice, but these animals exhibited a significant loss of the prominent frequency-facilitation expressed by the mossy fibre pathway. In addition to this change in short term synaptic plasticity, high frequency stimulation-induced, NMDA-receptor-independent LTP was absent in slices from the transgenic mice. These data represent the first description of functional deficits in the mossy fibre pathway of Aβ-overproducing transgenic mice.
    Full-text · Article · Nov 2010 · Molecular Brain
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by learning and memory function deterioration. While it is well established that exercise can improve cognitive performance in AD, there have been few basic cellular and molecular mechanisms research performed to test the interaction between exercise and AD. In this study, we aimed at investigating whether treadmill exercise improves learning and memory function in APP/PS1 transgenic mouse model of Alzheimer's disease by enhancing long-term potentiation (LTP) and up-regulation of brain-derived neurotrophic factor (BDNF) mRNA expression. Our results show that, in comparison to wild type mice, transgenic mice were characterized by impaired learning and memory function, LTP deficits and increased BDNF mRNA levels. Treadmill exercise enhanced learning and memory function not only in wild type mice but also in APP/PS1 mice paralleled by LTP. However, BDNF has emerged as a crucial regulator of synaptic plasticity mechanisms underlying learning and memory in wild-type mice, but not in APP/PS1 mice. Hence, this investigation demonstrates that treadmill exercise is an effective therapeutic that alleviate learning and memory decline in APP/PS1 mouse model, and enhanced LTP maybe a cellular mechanism involved in neuropathological course of AD and cognitive improvement induced by exercise.
    No preview · Article · Apr 2011 · Behavioural brain research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transgenic (Tg) mouse models of Alzheimer's disease (AD) are used to investigate mechanisms underlying disease pathology and identify therapeutic strategies. Most Tg AD models, which at least partly recapitulate the AD phenotype, are based on insertion of one or more human mutations (identified in Familial AD) into the mouse genome, with the notable exception of the anti-NGF mouse, which is based on the cholinergic unbalance hypothesis. It has recently emerged that impaired hippocampal synaptic function is an early detectable pathological alteration, well before the advanced stage of amyloid plaque accumulation and general cell death. Nevertheless, electrophysiological studies performed on different Tg models or on the same model by different research groups have yielded contrasting results. We therefore summarized data from original research papers studying hippocampal synaptic function using electrophysiology, to review what we have learned so far. We analyzed results obtained using the following Tg models: (1) single/multiple APP mutations; (2) single presenilin (PS) mutations; (3) APPxPS1 mutations; (4) APPxPS1xtau mutations (3xTg); and (5) anti-NGF expressing (AD11) mice. We observed that the majority of papers focus on excitatory basic transmission and long-term potentiation, while few studies evaluate inhibitory transmission and long-term depression. We searched for common synaptic alterations in the various models that might underlie the memory deficits observed in these mice. We also considered experimental variables that could explain differences in the reported results and briefly discuss successful rescue strategies. These analyses should prove useful for future design of electrophysiology experiments to assess hippocampal function in AD mouse models.
    Full-text · Article · Jul 2011 · Reviews in the neurosciences
Show more