Alterations of synaptic and network functions in APP and APLP-deficient mice

我们想要阐明APP(及其片段)和APLP2对小鼠海马区生理功能的作用。因此，我们将结合我们互补的专业知识来研究由U·米勒提供的转基因动物和细胞。我们假设APP或APLP的缺陷会导致基线突触属性、兴奋-抑制-平衡、短期和长期突触可塑性的变化，从而导致与记忆相关的网络活动的不同模式。致命的APP/APLP2-DKO双突变体的细胞将在海马细胞培养中进行分析。抑制性和兴奋性突触电流的预期变化将作为进一步在脑片上进行实验的基线，使用可行的APPα-KI/APLP2-KO突变小鼠。这些小鼠的异常将有助于揭示APP和APLP2的(重叠)功能。类似的分析将在APLP2-KO背景的条件性CamKlI-CreERT2 APPflx小鼠中进行，这些小鼠在他莫昔芬存在的情况下失去了前脑的APP。最后，三缺ES细胞(由M.Müler和B.DeStrooper产生)将被分化为神经元，并将在移植到器官型海马片培养后进行研究。总之，我们的数据将揭示APP/APLP蛋白家族在细胞和网络水平上的功能重要性。

We want to elucidate the role of APP (and its fragments) and APLP2 for physiological functions of the mouse hippocampus. Therefore, we will combine our complementary expertise to study genetically modified animals and cells, provided by U. Müller. We hypothesize that deficiency in APP or APLP causes changes in baseline synaptic properties, excitation-inhibition-balance, short- and long-term synaptic plasticity and, as a consequence, in different patterns of memory-related network activity. Cells from the lethal APP/APLP2- DKO double mutants will be analyzed in hippocampal cell cultures. The expected alterations of inhibitory and excitatory synaptic currents will serve as a baseline for further experiments on brain slices, using viable APPsα-KI/APLP2-KO mutant mice. Abnormalities in these mice will shed light on the (overlapping) function of APP and APLP2. A similar analysis will be done in conditional CamKlI-CreERT2 APPflox mice on an APLP2-KO background which lose APP in the forebrain in the presence of tamoxifen. Finally, triple-deficient ES cells (generated by U. Müller and B. DeStrooper) will be differentiated into neurons and will be studied after transplantation into organotypic hippocampal slice cultures. Together, our data shall reveal the functional importance of the APP/APLP protein family at the cellular and network level.