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.
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