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

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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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All Science Journal Classification (ASJC) codes

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

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