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

Zheng Wu, Ziyuan Guo, Marla Gearing, Gong Chen

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

Original languageEnglish (US)
Article number4159
JournalNature communications
Volume5
DOIs
StatePublished - Jun 13 2014

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Long-Term Memory
Long-Term Potentiation
Dentate Gyrus
gamma-Aminobutyric Acid
Alzheimer Disease
Data storage equipment
Astrocytes
Memory Disorders
mice
GABA Plasma Membrane Transport Proteins
transporter
biomarkers
impairment
Amyloid Plaques
Biomarkers
varespladib methyl
Amyloid
brain
Inhibition (Psychology)
therapy

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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abstract = "Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer' s disease (AD); however, reducing A{\^I} 2 production failed to relieve the symptoms of AD patients. Here we report a high GABA ({\^I} 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.",
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Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer' s disease model. / Wu, Zheng; Guo, Ziyuan; Gearing, Marla; Chen, Gong.

In: Nature communications, Vol. 5, 4159, 13.06.2014.

Research output: Contribution to journalArticle

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AB - 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.

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