Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. Despite its importance, the role of APP family in neuronal function and survival remains unclear because of perinatal lethality exhibited by knockout mice lacking all three APP family members. Here we report that selective inactivation of APP family members in excitatory neurons of the postnatal forebrain results in neither cortical neurodegeneration nor increases in apoptosis and gliosis up to ∼2 years of age. However, hippocampal synaptic plasticity, learning, and memory are impaired in these mutant mice. Furthermore, hippocampal neurons lacking APP family exhibit hyperexcitability, as evidenced by increased neuronal spiking in response to depolarizing current injections, whereas blockade of Kv7 channels mimics and largely occludes the effects of APP family inactivation. These findings demonstrate that APP family is not required for neuronal survival and suggest that APP family may regulate neuronal excitability through Kv7 channels.

淀粉样前体蛋白 (APP) 与家族性和散发性阿尔茨海默病有关。尽管 APP 家族很重要，但它在神经元功能和存活中的作用仍不清楚，因为缺乏所有三个 APP 家族成员的敲除小鼠表现出围产期致死率。在这里，我们报告说，出生后前脑兴奋性神经元中 APP 家族成员的选择性失活既不会导致皮质神经变性，也不会导致细胞凋亡和神经胶质增生的增加，直至 2 岁。然而，这些突变小鼠的海马突触可塑性、学习和记忆能力受到损害。此外，缺乏 APP 家族的海马神经元表现出过度兴奋，这可以通过响应去极化电流注射而增加的神经元尖峰来证明，而 Kv7 通道的阻断模仿并在很大程度上阻断 APP 家族失活的影响。这些发现表明 APP 家族不是神经元存活所必需的，并表明 APP 家族可能通过 Kv7 通道调节神经元兴奋性。