It has been proposed that Amyloid β Precursor Protein (APP) might act as a rheostat controlling neuronal excitability, but mechanisms have remained untested. APP and its catabolite Aβ are known to impact upon synapse function and dysfunction via their interaction with the prion protein (PrPC), suggesting a candidate pathway. Here we test if PrPC is required for this APP function in vivo, perhaps via modulating mGluR5 ion channels. We engineered zebrafish to lack homologs of PrPC and APP, allowing us to assess their purported genetic and physiological interactions in CNS development. We generated four appa null alleles as well as prp1-/-;appa-/- double mutants (engineering of prp1 mutant alleles is described elsewhere). Unexpectedly, appa-/- and compound prp1-/-;appa-/- mutants are viable and lacked overt phenotypes (except being slightly smaller than wildtype fish at some developmental stages). Zebrafish prp1-/- mutants were substantially more sensitive to appa knockdown than wildtype fish, and both zebrafish prp1 and mammalian Prnp mRNA were significantly able to partially rescue this effect. Further, appa-/- mutants exhibited increased seizures upon exposure to low doses of convulsant. The mechanism of this seizure susceptibility requires prp1 insomuch that seizures were significantly dampened to wildtype levels in prp1-/-;appa-/- mutants. Inhibiting mGluR5 channels, which may be downstream of PrPC, increased seizure intensity only in prp1-/- mutants, and this seizure mechanism required intact appa. Taken together, these results support an intriguing genetic interaction between prp1 and appa with their shared roles impacting upon neuron hyperexcitability, thus complementing and extending past works detailing their biochemical interaction(s).

中文翻译：

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淀粉样蛋白-β前体蛋白突变斑马鱼表现出依赖于ion病毒蛋白的癫痫发作敏感性。

有人提出淀粉样β前体蛋白（APP）可能起变阻器控制神经元兴奋性的作用，但机制尚未得到验证。已知APP及其分解代谢物Aβ通过与with病毒蛋白（PrPC）的相互作用而影响突触功能和功能障碍，这表明了候选途径。在这里，我们可能通过调节mGluR5离子通道来测试该PC功能是否在体内需要PrPC。我们对斑马鱼进行了工程改造，使其缺乏PrPC和APP的同源物，从而使我们能够评估它们在中枢神经系统发育中声称的遗传和生理相互作用。我们生成了四个appa null等位基因以及prp1-/-; appa-/-double突变体（其他地方介绍了prp1突变体等位基因的工程设计）。出乎意料的是，appa-/-和化合物prp1-/-; app /-/突变体是可行的，并且缺乏明显的表型（除了在某些发育阶段比野生型鱼稍小）。斑马鱼的prp1-/-突变体比野生型鱼类对appa击倒的敏感性高得多，并且斑马鱼的prp1和哺乳动物的Prnp mRNA都能够部分挽救这种效应。此外，appa //-突变体在暴露于低剂量惊厥剂后表现出癫痫发作增加。这种癫痫发作易感性的机制需要prp1极大，以致癫痫发作会大大抑制prp1-/-; appa-/-突变体中的野生型水平。抑制mGluR5通道（可能位于PrPC的下游），仅在prp1-/-突变体中增加了癫痫发作的强度，这种癫痫发作的机制需要完整的appa。在一起