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

Zheng Wu, Ziyuan Guo, Marla Gearing and Gong Chen ()
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Zheng Wu: Huck Institutes of Life Sciences, The Pennsylvania State University, University Park
Ziyuan Guo: Huck Institutes of Life Sciences, The Pennsylvania State University, University Park
Marla Gearing: Alzheimer’s Disease Research Center, Emory University School of Medicine
Gong Chen: Huck Institutes of Life Sciences, The Pennsylvania State University, University Park

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5159

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