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.