摘要Cleavage of amyloid precursor protein(APP)produces toxic amyloid-beta peptides,which play a critical role in the pathogenesis of Alzheimer's disease.Neuronal loss is a key feature of Alzheimer's disease.Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus,little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons.Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer's disease model mice with App knockout(App-/-),we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection,but did not affect their intrinsic excitability or miniature current activity.In contrast,at 10 weeks post-injection,adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology,increased miniature excitatory-and inhibitory-synaptic transmission,and decreased potassium-chloride-cotransporter 2 expression.Compared with adult-born granule cells at 10 week post-injection,mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App-/-mice.Additionally,although App-/-mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning,adult-born granule cells were not recruited in either App-/-or wild-type control mice.Taken together,these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection,promoting subsequent apoptosis of mature granule cells.