Prefrontal Cortical GABAergic Dysfunction Contributes to Aberrant UP-State Duration in APP Knockout Mice.

Genetic and biochemical studies have focused on the role of amyloid beta protein in the pathogenesis of Alzheimer's disease. In comparison, the physiological roles of its precursor protein, amyloid precursor protein (APP), in synaptic and network activity is less well studied. Using an APP knockout (APP(-/-)) mouse model, we show that the duration of UP state, which is a key feature of cortical synaptic integration occurring predominantly during slow-wave sleep, is significantly increased in the prefrontal cortex (PFC) in the absence of APP. This was accompanied by a specific reduction in the glutamine synthetase and tissue GABA content and sequential upregulation in the levels of GABA(B)R expression. Pharmacological reinforcement of GABA signaling by application of either a GABA uptake inhibitor or an agonist of GABA(B)R rescued the abnormality of UP-state duration and the former rescues altered GABA(B)R expression as well. In addition to revealing an essential role of APP in the regulation of PFC network function, this study evidences the viability of GABA signaling pathway and its receptors, especially GABA(B)Rs, as a target for the treatment of aberrant neural network activity and thus information processing.