Parent A, Linden D J, Sisodia S S, Borchelt D R
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Neurobiol Dis. 1999 Feb;6(1):56-62. doi: 10.1006/nbdi.1998.0207.
Mutations in two related genes, presenilin 1 and presenilin 2 (PS1 and PS2), cause a subset of early-onset familial Alzheimer's disease (FAD). PS1 is expressed in a variety of neuronal and peripheral tissues, including neuronal populations known to be at risk in Alzheimer's disease such as CA1 hippocampal neurons. To examine whether FAD-linked mutations in PS1 directly influence the physiology of learning and memory, we measured the field excitatory postsynaptic potential (fEPSP) at the Schaffer collateral-CA1 synapse in hippocampal slices. Basal synaptic transmission and long-term potentiation (LTP) were examined in neurons of transgenic mice expressing wild-type human PS1 (WtTg) and FAD-linked A246E PS1 variant (MTg) and in neurons of nontransgenic littermates (NTg). Several measures of basal synaptic transmission were unaltered in WtTg and MTg compared to NTg mice, including maximum fEPSP slope, maximum fEPSP amplitude, maximum fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope, an index of basal synaptic strength. In addition, paired-pulse facilitation was not changed. However, upon theta burst stimulation or high-frequency stimulation, input-specific LTP in MTg animals had a larger initial amplitude and was more persistent than that in WtTg or NTg animals. These data suggest that the FAD-linked A246E variant of PS1 leads to higher degree of LTP induction in mice.
两个相关基因早老素1和早老素2（PS1和PS2）的突变会导致一部分早发性家族性阿尔茨海默病（FAD）。PS1在多种神经元和外周组织中表达，包括已知在阿尔茨海默病中处于风险的神经元群体，如海马CA1区神经元。为了研究PS1中与FAD相关的突变是否直接影响学习和记忆的生理学，我们在海马切片的Schaffer侧支-CA1突触处测量了场兴奋性突触后电位（fEPSP）。在表达野生型人PS1（WtTg）和与FAD相关的A246E PS1变体（MTg）的转基因小鼠的神经元以及非转基因同窝小鼠（NTg）的神经元中检测了基础突触传递和长时程增强（LTP）。与NTg小鼠相比，WtTg和MTg小鼠的几种基础突触传递指标没有改变，包括最大fEPSP斜率、最大fEPSP幅度、最大纤维群峰电位幅度以及将纤维群峰电位幅度与fEPSP斜率相关联的函数，这是基础突触强度的一个指标。此外，双脉冲易化也没有变化。然而，在theta爆发刺激或高频刺激后，MTg动物的输入特异性LTP的初始幅度更大，并且比WtTg或NTg动物的更持久。这些数据表明，PS1的与FAD相关的A246E变体导致小鼠中更高程度的LTP诱导。
