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Nat Med. 2014 Aug;20(8):886-96. doi: 10.1038/nm.3639. Epub 2014 Jun 29.

GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease.

Author information

1
1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. [2] WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. [3].
2
1] WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. [2].
3
Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Republic of Korea.
4
1] WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. [2] Neuroscience Program, Korea University of Science and Technology, Daejeon, Republic of Korea.
5
1] Neuroscience Program, Korea University of Science and Technology, Daejeon, Republic of Korea. [2] Center for Neuroscience, Brain Science Institute, KIST, Seoul, Republic of Korea.
6
WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
7
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
8
Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
9
Center for Neuroscience, Brain Science Institute, KIST, Seoul, Republic of Korea.
10
Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
11
1] Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA. [2] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. [3] VA Boston Healthcare System, Boston, Massachusetts, USA.
12
1] Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Republic of Korea. [2] Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA. [3] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. [4] VA Boston Healthcare System, Boston, Massachusetts, USA.
13
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
14
1] WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. [2] Neuroscience Program, Korea University of Science and Technology, Daejeon, Republic of Korea. [3] Center for Neuroscience, Brain Science Institute, KIST, Seoul, Republic of Korea. [4] KU-KIST Graduate School of Converging Science of Technology, Korea University, Seoul, Republic of Korea.

Abstract

In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.

PMID:
24973918
DOI:
10.1038/nm.3639
[Indexed for MEDLINE]

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