title: GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease.
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.
authors: 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].
authors: Seonmi
authors: S
authors: Jo
authors: 1] WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. [2].
authors: Oleg
authors: O
authors: Yarishkin
authors: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Republic of Korea.
authors: Yu Jin
authors: YJ
authors: Hwang
authors: 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.
authors: Ye Eun
authors: YE
authors: Chun
authors: 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.
authors: Mijeong
authors: M
authors: Park
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Dong Ho
authors: DH
authors: Woo
authors: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
authors: Jin Young
authors: JY
authors: Bae
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Taekeun
authors: T
authors: Kim
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Jaekwang
authors: J
authors: Lee
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Heejung
authors: H
authors: Chun
authors: Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Hyun Jung
authors: HJ
authors: Park
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Da Yong
authors: DY
authors: Lee
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Jinpyo
authors: J
authors: Hong
authors: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Republic of Korea.
authors: Hye Yun
authors: HY
authors: Kim
authors: Center for Neuroscience, Brain Science Institute, KIST, Seoul, Republic of Korea.
authors: Soo-Jin
authors: SJ
authors: Oh
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Seung Ju
authors: SJ
authors: Park
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Hyo
authors: H
authors: Lee
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Bo-Eun
authors: BE
authors: Yoon
authors: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Republic of Korea.
authors: YoungSoo
authors: 0000000150297082
authors: Y
authors: Kim
authors: Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
authors: Yong
authors: Y
authors: Jeong
authors: Department of Science in Korean Medicine, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Insop
authors: I
authors: Shim
authors: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
authors: Yong Chul
authors: YC
authors: Bae
authors: 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.
authors: Jeiwon
authors: J
authors: Cho
authors: 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.
authors: Neil W
authors: NW
authors: Kowall
authors: 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.
authors: Hoon
authors: H
authors: Ryu
authors: WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors: Eunmi
authors: E
authors: Hwang
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors: Daesoo
authors: D
authors: Kim
authors: 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.
authors: C Justin
authors: CJ
authors: Lee
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000075002:Bestrophins; D002531:Cerebellum / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018756:GABA Antagonists / Q000627:therapeutic use; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D018079:Receptors, GABA / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
chemical_list: D016229:Amyloid beta-Peptides; C491856:Best1 protein, mouse; D000075002:Bestrophins; D005136:Eye Proteins; D018756:GABA Antagonists; D007473:Ion Channels; D008996:Monoamine Oxidase Inhibitors; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D018079:Receptors, GABA; C075222:amyloid beta-protein (1-42); D005680:gamma-Aminobutyric Acid; D008995:Monoamine Oxidase; D053829:Amyloid Precursor Protein Secretases; D011700:Putrescine