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

我们希望阐明APP（及其片段）和APLP 2的作用，小鼠海马的生理功能。因此，我们将联合收割机结合我们互补的专业知识，研究转基因动物和细胞，由美国提供。穆勒我们假设APP或APLP的缺乏会导致基线突触特性，兴奋-抑制-平衡，短期和长期突触可塑性的变化，因此，在不同模式的记忆相关的网络活动。将在海马细胞培养物中分析来自致死APP/APLP 2- DKO双突变体的细胞。抑制性和兴奋性突触电流的预期变化将作为使用存活APP α-KI/APLP 2-KO突变小鼠对脑切片进行进一步实验的基线。在这些小鼠中的脱落将揭示APP和APLP 2的（重叠）功能。将在APLP 2-KO背景的条件性CamKlI-CreERT 2 APPflox小鼠中进行类似的分析，所述小鼠在他莫昔芬的存在下前脑中丢失APP。最后，三缺陷ES细胞（由U. Müller和B。DeStrooper）将分化成神经元，并在移植到器官型海马切片培养物中后进行研究。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.