Tonic inhibition in dentate gyrus impairs long- term potentiation and memory in an Alzhiemer's disease model

• Type of Material: Article
• Authors: Zheng Wu, Pennsylvania State University; Ziyuan Guo, Pennsylvania State University; Marla Gearing, Emory University; Gong Chen, Pennsylvania State University
• Language: English
• Date: 2014-06-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms5159
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 5
• Start Page: 4159
• End Page: 4159
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (MH083911 and AG045656) and Pennsylvania State University Eberly College of Science Stem Cell Fund to G.C. M.G. was supported by NIH grants P50 AG025688 and P30 NS055077.
• Keywords: Science & Technology - Other Topics; Multidisciplinary Sciences; SYNAPTIC PLASTICITY; DEFICITS; NEUROPATHOLOGIC ASSESSMENT; IN-VIVO; MULTIDISCIPLINARY SCIENCES; α5 subunit; RAT HIPPOCAMPUS; MICE; GAT3; GLUTAMATE UPTAKE; ASTROCYTE; GABA(A) RECEPTOR; Science & Technology; ALZHEIMERS-DISEASE; GAT4
• Research Categories: Health Sciences, General; Health Sciences, Pathology

Abstract

Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer' s disease (AD); however, reducing AÎ 2 production failed to relieve the symptoms of AD patients. Here we report a high GABA (Î 3-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.