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

Research output: Contribution to journalReview article

230 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 languageEnglish
Pages (from-to)886-896
Number of pages11
JournalNature Medicine
Volume20
Issue number8
DOIs
Publication statusPublished - 2014 Jan 1

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Astrocytes
gamma-Aminobutyric Acid
Alzheimer Disease
Data storage equipment
Presynaptic Receptors
Neuronal Plasticity
GABA Receptors
Monoamine Oxidase
Dentate Gyrus
Amyloid Plaques
Amyloid
Plasticity
Brain
Learning

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jo, S., Yarishkin, O., Hwang, Y. J., Chun, Y. E., Park, M., Woo, D. H., ... 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, Seonmi ; Yarishkin, Oleg ; Hwang, Yu Jin ; Chun, Ye Eun ; Park, Mijeong ; Woo, Dong Ho ; Bae, Jin Young ; Kim, Taekeun ; Lee, Jaekwang ; Chun, Heejung ; Park, Hyun Jung ; Lee, Da Yong ; Hong, Jinpyo ; Kim, Hye Yun ; Oh, Soo Jin ; Park, Seung Ju ; Lee, Hyo ; Yoon, Bo Eun ; Kim, YoungSoo ; Jeong, Yong ; Shim, Insop ; Bae, Yong Chul ; Cho, Jeiwon ; Kowall, Neil W. ; Ryu, Hoon ; Hwang, Eunmi ; Kim, Daesoo ; Lee, C. Justin. / GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. In: Nature Medicine. 2014 ; Vol. 20, No. 8. pp. 886-896.
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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.",
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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

GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. / Jo, Seonmi; Yarishkin, Oleg; Hwang, Yu Jin; Chun, Ye Eun; Park, Mijeong; Woo, Dong Ho; Bae, Jin Young; Kim, Taekeun; Lee, Jaekwang; Chun, Heejung; Park, Hyun Jung; Lee, Da Yong; Hong, Jinpyo; Kim, Hye Yun; Oh, Soo Jin; Park, Seung Ju; Lee, Hyo; Yoon, Bo Eun; Kim, YoungSoo; Jeong, Yong; Shim, Insop; Bae, Yong Chul; Cho, Jeiwon; Kowall, Neil W.; Ryu, Hoon; Hwang, Eunmi; Kim, Daesoo; Lee, C. Justin.

In: Nature Medicine, Vol. 20, No. 8, 01.01.2014, p. 886-896.

Research output: Contribution to journalReview article

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AU - Chun, Heejung

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AU - Shim, Insop

AU - Bae, Yong Chul

AU - Cho, Jeiwon

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Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nature Medicine. 2014 Jan 1;20(8):886-896. https://doi.org/10.1038/nm.3639