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

Seonmi Jo; Oleg Yarishkin; Yu Jin Hwang; Ye Eun Chun; Mijeong Park; Dong Ho Woo; Jin Young Bae; Taekeun Kim; Jaekwang Lee; Heejung Chun; Hyun Jung Park; Da Yong Lee; Jinpyo Hong; Hye Yun Kim; Soo Jin Oh; Seung Ju Park; Hyo Lee; Bo Eun Yoon; Youngsoo Kim; Yong Jeong; Insop Shim; Yong Chul Bae; Jeiwon Cho; Neil W. Kowall; Hoon Ryu; Eunmi Hwang; Daesoo Kim; C. Justin Lee

doi:10.1038/nm.3639

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

Seonmi Jo
, Oleg Yarishkin
, Yu Jin Hwang
, Ye Eun Chun
, Mijeong Park
, Dong Ho Woo
, Jin Young Bae
, Taekeun Kim
, Jaekwang Lee
, Heejung Chun
, Hyun Jung Park
, Da Yong Lee
, Jinpyo Hong
, Hye Yun Kim
, Soo Jin Oh
, Seung Ju Park
, Hyo Lee
, Bo Eun Yoon
, Youngsoo Kim
, Yong Jeong

Insop Shim, Yong Chul Bae, Jeiwon Cho, Neil W. Kowall, Hoon Ryu, Eunmi Hwang, Daesoo Kim^*, C. Justin Lee

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

668 Citations (Scopus)

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.

Original language	English
Pages (from-to)	886-896
Number of pages	11
Journal	Nature Medicine
Volume	20
Issue number	8
DOIs	https://doi.org/10.1038/nm.3639
Publication status	Published - 2014 Aug

Bibliographical note

Funding Information:
This work was supported by the WCI Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP: to C.J.L., NRF grant number: WCI 2009-003), the KIST Institutional Flagship Program (to C.J.L., 3E25022; to H.R., 2E24380), the National Leading Research Laboratory Program of Korea and the KAIST Future Systems Healthcare Project (to D.K., NRF grant number: 2011-0028772), the Basic Science Research Program through the NRF funded by the MSIP (to Y.C.B., 2008-0062282), and the National Institute of Aging of USA (to N.W.K.). We thank Mazence for APP/PS1 mice, W. Park (GIST) for 5XFAD mice, K. Park and H. Song (KIST) for safinamide and K. Fujiwara (Sojo University) for the putrescine-specific antibody.

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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Jo, S., Yarishkin, O., Hwang, Y. J., Chun, Y. E., Park, M., Woo, D. H., Bae, J. Y., Kim, T., Lee, J., Chun, H., Park, H. J., Lee, D. Y., Hong, J., Kim, H. Y., Oh, S. J., Park, S. J., Lee, H., Yoon, B. E., Kim, Y., ... Lee, C. J. (2014). GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nature Medicine, 20(8), 886-896. https://doi.org/10.1038/nm.3639

Jo, S, Yarishkin, O, Hwang, YJ, Chun, YE, Park, M, Woo, DH, Bae, JY, Kim, T, Lee, J, Chun, H, Park, HJ, Lee, DY, Hong, J, Kim, HY, Oh, SJ, Park, SJ, Lee, H, Yoon, BE, Kim, Y, Jeong, Y, Shim, I, Bae, YC, Cho, J, Kowall, NW, Ryu, H, Hwang, E, Kim, D & Lee, CJ 2014, 'GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease', Nature Medicine, vol. 20, no. 8, pp. 886-896. https://doi.org/10.1038/nm.3639

@article{8640c705926e4f5a87bcb70d343b5f0c,

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.",

author = "Seonmi Jo and Oleg Yarishkin and Hwang, \{Yu Jin\} and Chun, \{Ye Eun\} and Mijeong Park and Woo, \{Dong Ho\} and Bae, \{Jin Young\} and Taekeun Kim and Jaekwang Lee and Heejung Chun and Park, \{Hyun Jung\} and Lee, \{Da Yong\} and Jinpyo Hong and Kim, \{Hye Yun\} and Oh, \{Soo Jin\} and Park, \{Seung Ju\} and Hyo Lee and Yoon, \{Bo Eun\} and Youngsoo Kim and Yong Jeong and Insop Shim and Bae, \{Yong Chul\} and Jeiwon Cho and Kowall, \{Neil W.\} and Hoon Ryu and Eunmi Hwang and Daesoo Kim and Lee, \{C. Justin\}",

note = "Funding Information: This work was supported by the WCI Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP: to C.J.L., NRF grant number: WCI 2009-003), the KIST Institutional Flagship Program (to C.J.L., 3E25022; to H.R., 2E24380), the National Leading Research Laboratory Program of Korea and the KAIST Future Systems Healthcare Project (to D.K., NRF grant number: 2011-0028772), the Basic Science Research Program through the NRF funded by the MSIP (to Y.C.B., 2008-0062282), and the National Institute of Aging of USA (to N.W.K.). We thank Mazence for APP/PS1 mice, W. Park (GIST) for 5XFAD mice, K. Park and H. Song (KIST) for safinamide and K. Fujiwara (Sojo University) for the putrescine-specific antibody.",

year = "2014",

month = aug,

doi = "10.1038/nm.3639",

language = "English",

volume = "20",

pages = "886--896",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "8",

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T1 - GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease

AU - Jo, Seonmi

AU - Yarishkin, Oleg

AU - Hwang, Yu Jin

AU - Chun, Ye Eun

AU - Park, Mijeong

AU - Woo, Dong Ho

AU - Bae, Jin Young

AU - Kim, Taekeun

AU - Lee, Jaekwang

AU - Chun, Heejung

AU - Park, Hyun Jung

AU - Lee, Da Yong

AU - Hong, Jinpyo

AU - Kim, Hye Yun

AU - Oh, Soo Jin

AU - Park, Seung Ju

AU - Lee, Hyo

AU - Yoon, Bo Eun

AU - Kim, Youngsoo

AU - Jeong, Yong

AU - Shim, Insop

AU - Bae, Yong Chul

AU - Cho, Jeiwon

AU - Kowall, Neil W.

AU - Ryu, Hoon

AU - Hwang, Eunmi

AU - Kim, Daesoo

AU - Lee, C. Justin

N1 - Funding Information: This work was supported by the WCI Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP: to C.J.L., NRF grant number: WCI 2009-003), the KIST Institutional Flagship Program (to C.J.L., 3E25022; to H.R., 2E24380), the National Leading Research Laboratory Program of Korea and the KAIST Future Systems Healthcare Project (to D.K., NRF grant number: 2011-0028772), the Basic Science Research Program through the NRF funded by the MSIP (to Y.C.B., 2008-0062282), and the National Institute of Aging of USA (to N.W.K.). We thank Mazence for APP/PS1 mice, W. Park (GIST) for 5XFAD mice, K. Park and H. Song (KIST) for safinamide and K. Fujiwara (Sojo University) for the putrescine-specific antibody.

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84905822105

U2 - 10.1038/nm.3639

DO - 10.1038/nm.3639

M3 - Review article

C2 - 24973918

AN - SCOPUS:84905822105

SN - 1078-8956

VL - 20

SP - 886

EP - 896

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

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

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