title: Prefrontal Cortical GABAergic Dysfunction Contributes to Aberrant UP-State Duration in APP Knockout Mice.
abstract: Genetic and biochemical studies have focused on the role of amyloid β 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 GABABR expression. Pharmacological reinforcement of GABA signaling by application of either a GABA uptake inhibitor or an agonist of GABABR rescued the abnormality of UP-state duration and the former rescues altered GABABR 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 GABABRs, as a target for the treatment of aberrant neural network activity and thus information processing.
authors.affiliation: School of Psychology South China Normal University, Guangzhou 510631, China.|School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Huo
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: He
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Jin
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou 510631, China.|Brain Science Institute, South China Normal University, Guangzhou 510631, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Long
authors.affiliation: School of Psychology South China Normal University, Guangzhou 510631, China.|Brain Science Institute, South China Normal University, Guangzhou 510631, China.|Center for Studies of Psychological Application, South China Normal University, Guangzhou 510631, China.|Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D016229:Amyloid beta-Peptides / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D005260:Female; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D012919:Social Behavior; D013997:Time Factors; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D005974:Glutamate-Ammonia Ligase
keywords: GABABR; UP states; amyloid precursor protein; glutamine synthetase; prefrontal cortex