title: Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer's [corrected] disease model.
abstract: Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer's disease (AD); however, reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhances tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for AD.
authors.affiliation: Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Pathology and Laboratory Medicine, Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid