Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased tonic GABA release and GABA immunoreactivity in reactive astrocytes.
Figure 2: GABA is released from reactive astrocytes via redistributed Best1 channel.
Figure 3: Maob is responsible for GABA production in reactive astrocytes.
Figure 4: Maob-mediated production and Best1-mediated release of GABA in cultured hippocampal astrocytes.
Figure 5: Impaired presynaptic release probability, spike probability, synaptic plasticity, and learning and memory are fully rescued by targeting Maob or Best1.
Figure 6: Clinical relevance of GABA from reactive astrocytes.

Similar content being viewed by others

References

  1. Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 8, 131–168 (2012).

  2. Mattson, M.P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mucke, L. & Selkoe, D.J. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2, a006338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ballatore, C., Lee, V.M.-Y. & Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Eddleston, M. & Mucke, L. Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54, 15–36 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Wisniewski, H.M. & Wegiel, J. Spatial relationships between astrocytes and classical plaque components. Neurobiol. Aging 12, 593–600 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Sofroniew, M.V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuchibhotla, K.V., Lattarulo, C.R., Hyman, B.T. & Bacskai, B.J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Woo, D.H. et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 151, 25–40 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Henneberger, C., Papouin, T., Oliet, S.H. & Rusakov, D.A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blum, A.E., Joseph, S.M., Przybylski, R.J. & Dubyak, G.R. Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes. Am. J. Physiol. Cell Physiol. 295, C231–C241 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790–796 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Samakashvili, S. et al. Analysis of chiral amino acids in cerebrospinal fluid samples linked to different stages of Alzheimer disease. Electrophoresis 32, 2757–2764 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Yoshiike, Y. et al. GABAA Receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3, e3029 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yoon, B.E. et al. The amount of astrocytic GABA positively correlates with the degree of tonic inhibition in hippocampal CA1 and cerebellum. Mol. Brain 4, 42 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Borchelt, D.R. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Kamphuis, W. et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS ONE 7, e42823 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Volianskis, A., Køstner, R., Mølgaard, M., Hass, S. & Jensen, M.S. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of β-amyloidosis. Neurobiol. Aging 31, 1173–1187 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Irizarry, M.C. et al. Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17, 7053–7059 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matousek, S.B. et al. Chronic IL-1β–mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer's disease without inducing overt neurodegeneration. J. Neuroimmune Pharmacol. 7, 156–164 (2012).

    Article  PubMed  Google Scholar 

  22. Hartlage-Rübsamen, M. et al. Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 121, 705–719 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kesner, R.P. A behavioral analysis of dentate gyrus function. Prog. Brain Res. 163, 567–576 (2007).

    Article  PubMed  Google Scholar 

  24. Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cao, D., Lu, H., Lewis, T.L. & Li, L. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 282, 36275–36282 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Han, K.-S. et al. Channel-mediated astrocytic glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol. Brain 6, 4 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Park, H. et al. High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol. Brain 6, 54 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Seiler, N., Sshmidt-Glenewinkel, T. & Sarhan, S. On the formation of γ-aminobutyric acid from putrescine in brain. J. Biochem. 86, 277–279 (1979).

    CAS  PubMed  Google Scholar 

  29. Laschet, J., Grisar, T., Bureau, M. & Guillaume, D. Characteristics of putrescine uptake and subsequent GABA formation in primary cultured astrocytes from normal C57BL/6J and epileptic DBA/2J mouse brain cortices. Neuroscience 48, 151–157 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Caspi, R. et al. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res. 40, D742–D753 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Seiler, N. & Al-Therib, M. Putrescine catabolism in mammalian brain. Biochem. J. 144, 29–35 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Saura, J. et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62, 15–30 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura, S. et al. Expression of monoamine oxidase B activity in astrocytes of senile plaques. Acta Neuropathol. 80, 419–425 (1990).

    Article  CAS  PubMed  Google Scholar 

  34. Saura, J., Kettler, R., Da Prada, M. & Richards, J. Quantitative enzyme radioautography with 3H-Ro 41–1049 and 3H-Ro 19–6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain. J. Neurosci. 12, 1977–1999 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Levitt, P., Pintar, J.E. & Breakefield, X.O. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc. Natl. Acad. Sci. USA 79, 6385–6389 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Birkmayer, W., Riederer, P., Youdim, M. & Linauer, W. The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil. J. Neural Transm. 36, 303–326 (1975).

    Article  CAS  PubMed  Google Scholar 

  37. Youdim, M.B. et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J. Neurosci. Res. 79, 172–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Nägga, K., Bogdanovic, N. & Marcusson, J. GABA transporters (GAT-1) in Alzheimer's disease. J. Neural Transm. 106, 1141–1149 (1999).

    Article  PubMed  Google Scholar 

  39. Lee, J., Kannagi, M., Ferrante, R.J., Kowall, N.W. & Ryu, H. Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J. 23, 1739–1749 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Turrigiano, G.G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Allen, C. & Stevens, C.F. An evaluation of causes for unreliability of synaptic transmission. Proc. Natl. Acad. Sci. USA 91, 10380–10383 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gimbel, D.A. et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 30, 6367–6374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. De Angelis, L. & Furlan, C. The anxiolytic-like properties of two selective MAOIs, moclobemide and selegiline, in a standard and an enhanced light/dark aversion test. Pharmacol. Biochem. Behav. 65, 649–653 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Wilcock, G.K., Birks, J., Whitehead, A. & Evans, S.J. The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials. Int. J. Geriatr. Psychiatry 17, 175–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Engberg, G., Elebring, T. & Nissbrandt, H. Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons. J. Pharmacol. Exp. Ther. 259, 841–847 (1991).

    CAS  PubMed  Google Scholar 

  46. Marzo, A. et al. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol. Res. 50, 77–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Squire, L.R., Stark, C.E. & Clark, R.E. The medial temporal lobe*. Annu. Rev. Neurosci. 27, 279–306 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Palop, J.J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Pike, C.J., Cummings, B., Monzavi, R. & Cotman, C.W. β-amyloid–induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease. Neuroscience 63, 517–531 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, G. et al. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Scheff, S.W. & Price, D.A. Synaptic density in the inner molecular layer of the hippocampal dentate gyrus in Alzheimer disease. J. Neuropathol. Exp. Neurol. 57, 1146–1153 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Jacobs, K., Kharazia, V.N. & Prince, D.A. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res. 36, 165–188 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Piccinin, G.L., Finali, G. & Piccirilli, M. Neuropsychological effects of L-deprenyl in Alzheimer's type dementia. Clin. Neuropharmacol. 13, 147–163 (1990).

    Article  CAS  PubMed  Google Scholar 

  56. Tariot, P.N. et al. L-deprenyl in Alzheimer's disease: preliminary evidence for behavioral change with monoamine oxidase B inhibition. Arch. Gen. Psychiatry 44, 427–433 (1987).

    Article  CAS  PubMed  Google Scholar 

  57. Monteverde, A., Gnemmi, P., Rossi, F. & Finali, G. Selegiline in the treatment of mild to moderate Alzheimer-type dementia. Clin. Ther. 12, 315–322 (1990).

    CAS  PubMed  Google Scholar 

  58. Birks, J. & Flicker, L. Selegiline for Alzheimer's disease. Cochrane Database Syst. Rev. CD000442 (2003).

  59. Gerlach, M., Youdim, M. & Riederer, P. Pharmacology of selegiline. Neurology 47, S137–S145 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Barres, B.A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Paxinos, G. & Franklin, K. The Mouse Brain in Stereotaxic Coordinates: Compact Second Edition. (Academic Press, San Diego, 2003).

    Google Scholar 

  62. Kutlán, D. & Molnar-Perl, I. New aspects of the simultaneous analysis of amino acids and amines as their o-phthaldialdehyde derivatives by high-performance liquid chromatography. Analysis of wine, beer and vinegar. J. Chromatogr. A 987, 311–322 (2003).

    Article  PubMed  Google Scholar 

  63. Mengerink, Y., Kutlan, D., Toth, F., Csampai, A. & Molnar-Perl, I. Advances in the evaluation of the stability and characteristics of the amino acid and amine derivatives obtained with the o-phthaldialdehyde/3-mercaptopropionic acid and o-phthaldialdehyde/N-acetyl-L-cysteine reagents. High-performance liquid chromatography-mass spectrometry study. J. Chromatogr. A 949, 99–124 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, Y.S., Moss, J.A. & Janda, K.D. Biological tuning of synthetic tactics in solid-phase synthesis: Application to Aβ (1–42). J. Org. Chem. 69, 7776–7778 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Unal Cevik, I. & Dalkara, T. Intravenously administered propidium iodide labels necrotic cells in the intact mouse brain after injury. Cell Death Differ. 10, 928–929 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Park, H. et al. Bestrophin-1 encodes for the Ca2+-activated anion channel in hippocampal astrocytes. J. Neurosci. 29, 13063–13073 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fujiwara, K., Tanabe, T., Yabuuchi, M., Ueoka, R. & Tsuru, D. A monoclonal antibody against the glutaraldehyde-conjugated polyamine, putrescine: application to immunocytochemistry. Histochem. Cell Biol. 115, 471–477 (2001).

    CAS  PubMed  Google Scholar 

  68. Sehgal, N. et al. Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc. Natl. Acad. Sci. USA 109, 3510–3515 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hong, J. et al. Microglial Toll-like receptor 2 contributes to kainic acid-induced glial activation and hippocampal neuronal cell death. J. Biol. Chem. 285, 39447–39457 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

S.J., O.Y., D.K. and C.J.L. designed the study, analyzed the data and wrote the manuscript. O.Y. carried out most slice electrophysiology. Y.J.H., N.W.K. and H.R. performed human tissue experiments. Y.E.C. and D.H.W. performed sniffer patch. S.J., M.P. and J.C. performed behavior tests. J.Y.B. and Y.C.B. performed electron microscopy experiments. S.J., J.L. and H.C. contributed to GABA recording. H.J.P. and I.S. performed microdialysis and HPLC. E.H., D.Y.L. and J.H. contributed to molecular biology. H.Y.K. and Y.K. synthesized Aβ42 and performed oligomer western blotting. B.-E.Y. contributed to lentiviral Maob shRNA cloning. Y.J. contributed to discussion and to mouse breeding. S.J. conducted all the rest of the experiments with assistance from T.K., S.-J.O., S.J.P. and H.L. All authors contributed to analysis and discussion of the results.

Corresponding authors

Correspondence to Daesoo Kim or C Justin Lee.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Tables 1–3 (PDF 3928 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jo, S., Yarishkin, O., Hwang, Y. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nat Med 20, 886–896 (2014). https://doi.org/10.1038/nm.3639

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3639

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing