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Author Notes:

Correspondence and requests for materials should be addressed to G.C. (email: gongchen@psu.edu).

Z.W. performed the majority of experiments and did most of the data analysis.

Z.G. performed experiments on human hippocampal tissue and on some mouse tissue.

G.C. conceived and supervised the entire project, analysed the data and wrote the manuscript.

M.G. provided human hippocampal tissue.

We would like to thank Dr Ian Simpson, Dr Gangyi Wu and Kate Simpson for critical reading of the manuscript, and Chen lab members for rigorous discussion during the progress of this project.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • GABA(A) RECEPTOR
  • ALZHEIMERS-DISEASE
  • NEUROPATHOLOGIC ASSESSMENT
  • SYNAPTIC PLASTICITY
  • GLUTAMATE UPTAKE
  • RAT HIPPOCAMPUS
  • IN-VIVO
  • ASTROCYTE
  • MICE
  • DEFICITS
  • α5 subunit
  • GAT3
  • GAT4

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

Tools:

Journal Title:

Nature Communications

Volume:

Volume 5

Publisher:

, Pages 4159-4159

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2014 Macmillan Publishers Limited. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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