We re-examined the potential role of APP in synaptic function by focusing on dendritic spines in APP−/− neurons by both in vitro and in vivo approaches. First, we measured dendritic spine densities from hippocampal neurons cultured from P0-P1 neonatal pups from APP+/+, APP+/−, and APP−/− mice (Fig. 1A, B). The spine density in APP−/− neurons was significantly decreased by almost 40% compared to APP+/+ (36.8%, p < 0.001, one-way ANOVA with Tukey’s post-hoc test) and APP+/− (35%, p < 0.001). In this analysis, 45 neurons were scored from a total of 11 APP+/+ mice, 64 neurons from 15 APP+/− mice, and 85 neurons from 21 APP−/− mice. Thus, APP−/− primary hippocampal neurons in culture showed a markedly diminished dendritic spine number as a measure of synaptic density. There was, however, no appreciable difference between wild type and hemizygous APP-deficient neurons. Therefore, to simplify subsequent breeding for in vivo analyses, we have chosen to focus our comparison primarily between APP+/− and APP−/− mice. We also noticed a reduction of dendritic complexity in culture hippocampal neurons from APP deficient mice. However, in
