Article | Published:

Rescue of long-range circuit dysfunction in Alzheimer's disease models

Nature Neuroscience volume 18, pages 16231630 (2015) | Download Citation

Abstract

Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non–rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-β (Aβ) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an Aβ-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABAAergic inhibition identifies a synaptic mechanism underlying Aβ-dependent large-scale circuit dysfunction.

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References

  1. 1.

    & The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

  2. 2.

    , & Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat. Rev. Neurol. 10, 115–119 (2014).

  3. 3.

    et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 70, 587–593 (2013).

  4. 4.

    , , , & Sleep fragmentation and the risk of incident Alzheimer's disease and cognitive decline in older persons. Sleep 36, 1027–1032 (2013).

  5. 5.

    et al. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology. Sci. Transl. Med. 4, 150ra122 (2012).

  6. 6.

    , , , & The sleep slow oscillation as a traveling wave. J. Neurosci. 24, 6862–6870 (2004).

  7. 7.

    , & Origin of active states in local neocortical networks during slow sleep oscillation. Cereb. Cortex 20, 2660–2674 (2010).

  8. 8.

    et al. Making waves: initiation and propagation of corticothalamic Ca2+ waves in vivo. Neuron 77, 1136–1150 (2013).

  9. 9.

    , , , & Sequential structure of neocortical spontaneous activity in vivo. Proc. Natl. Acad. Sci. USA 104, 347–352 (2007).

  10. 10.

    , , & The slow (< 1 Hz) oscillation in reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J. Neurosci. 13, 3284–3299 (1993).

  11. 11.

    & Global intracellular slow-wave dynamics of the thalamocortical system. J. Neurosci. 34, 8875–8893 (2014).

  12. 12.

    , , & Communication between neocortex and hippocampus during sleep in rodents. Proc. Natl. Acad. Sci. USA 100, 2065–2069 (2003).

  13. 13.

    & Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat. Neurosci. 10, 100–107 (2007).

  14. 14.

    , , & Properties of slow oscillation during slow-wave sleep and anesthesia in cats. J. Neurosci. 31, 14998–15008 (2011).

  15. 15.

    & Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice. Nature 454, 881–885 (2008).

  16. 16.

    et al. The upshot of up states in the neocortex: from slow oscillations to memory formation. J. Neurosci. 27, 11838–11841 (2007).

  17. 17.

    & The memory function of sleep. Nat. Rev. Neurosci. 11, 114–126 (2010).

  18. 18.

    & Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81, 12–34 (2014).

  19. 19.

    Grouping of brain rhythms in corticothalamic systems. Neuroscience 137, 1087–1106 (2006).

  20. 20.

    & Sleep and the single neuron: the role of global slow oscillations in individual cell rest. Nat. Rev. Neurosci. 14, 443–451 (2013).

  21. 21.

    et al. Functional alterations in memory networks in early Alzheimer's disease. Neuromolecular Med. 12, 27–43 (2010).

  22. 22.

    et al. Bidirectional relationship between functional connectivity and amyloid-β deposition in mouse brain. J. Neurosci. 32, 4334–4340 (2012).

  23. 23.

    Two views of brain function. Trends Cogn. Sci. 14, 180–190 (2010).

  24. 24.

    et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321, 1686–1689 (2008).

  25. 25.

    et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 109, 8740–8745 (2012).

  26. 26.

    et al. Staged decline of neuronal function in vivo in an animal model of Alzheimer's disease. Nat. Commun. 3, 774 (2012).

  27. 27.

    , & In vivo calcium imaging of the aging and diseased brain. Eur. J. Nucl. Med. Mol. Imaging 35 (suppl. 1): S99–S106 (2008).

  28. 28.

    , , & In vivo two-photon calcium imaging of neuronal networks. Proc. Natl. Acad. Sci. USA 100, 7319–7324 (2003).

  29. 29.

    et al. Sound-evoked network calcium transients in mouse auditory cortex in vivo. J. Physiol. (Lond.) 590, 899–918 (2012).

  30. 30.

    & How local is the local field potential? Neuron 72, 847–858 (2011).

  31. 31.

    et al. Sparsification of neuronal activity in the visual cortex at eye-opening. Proc. Natl. Acad. Sci. USA 106, 15049–15054 (2009).

  32. 32.

    , , & Mirrored bilateral slow-wave cortical activity within local circuits revealed by fast bihemispheric voltage-sensitive dye imaging in anesthetized and awake mice. J. Neurosci. 30, 3745–3751 (2010).

  33. 33.

    , & Differential responses of hippocampal subfields to cortical up-down states. Proc. Natl. Acad. Sci. USA 104, 5169–5174 (2007).

  34. 34.

    & The slow (<1 Hz) rhythm of non-REM sleep: a dialogue between three cardinal oscillators. Nat. Neurosci. 13, 9–17 (2010).

  35. 35.

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

  36. 36.

    & Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat. Neurosci. 3, 1027–1034 (2000).

  37. 37.

    & The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425–429 (1997).

  38. 38.

    Resolving controversies on the path to Alzheimer's therapeutics. Nat. Med. 17, 1060–1065 (2011).

  39. 39.

    et al. Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia. Neuron 76, 526–533 (2012).

  40. 40.

    & Neuronal hyperactivity – a key defect in Alzheimer's disease? Bioessays 37, 624–632 (2015).

  41. 41.

    et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922 (2005).

  42. 42.

    et al. Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch. Neurol. 69, 51–58 (2012).

  43. 43.

    et al. Effects of synaptic modulation on β-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J. Neurosci. 30, 14299–14304 (2010).

  44. 44.

    , , , & A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 29, 639–658 (2012).

  45. 45.

    et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. Br. Med. J. 349, g5205 (2014).

  46. 46.

    , & Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis. Assoc. Disord. 12, 14–17 (1998).

  47. 47.

    , , & Light sleep versus slow wave sleep in memory consolidation: a question of global versus local processes? Trends Neurosci. 37, 10–19 (2014).

  48. 48.

    et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J. Neurosci. 30, 13707–13717 (2010).

  49. 49.

    & Low-frequency (< 1 Hz) oscillations in the human sleep electroencephalogram. Neuroscience 81, 213–222 (1997).

  50. 50.

    , & Scaling brain size, keeping timing: evolutionary preservation of brain rhythms. Neuron 80, 751–764 (2013).

  51. 51.

    , , & Component analysis reveals sharp tuning of the local field potential in the guinea pig auditory cortex. J. Neurophysiol. 109, 261–272 (2013).

  52. 52.

    & The Mouse Brain in Stereotaxic Coordinates (Academic, 2001).

  53. 53.

    Absence of rapid sensory adaptation in neocortex during information processing states. Neuron 41, 455–464 (2004).

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Acknowledgements

We thank C. Tischbirek for assistance with graphics, A. Beazley for help with data analysis and M. Staufenbiel for discussions and comments. This work was funded by an Advanced European Research Council grant to A.K., the European Union FP7 program (Project Corticonic) and the Deutsche Forschungsgemeinschaft (RTG 1373 and SFB870). M.A.B. was supported by the Langmatz Stiftung. I.N. was supported by a grant from the Israel Science Foundation and by the Deutsche Forschungsgemeinschaft (SFB870).

Author information

Affiliations

  1. Institute of Neuroscience, Technische Universität München, Munich, Germany.

    • Marc Aurel Busche
    • , Maja Kekuš
    • , Helmuth Adelsberger
    • , Takahiro Noda
    •  & Arthur Konnerth
  2. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.

    • Marc Aurel Busche
    •  & Hans Förstl
  3. Munich Cluster for Systems Neurology (SyNergy) and Center for Integrated Protein Science Munich (CIPSM), Munich, Germany.

    • Marc Aurel Busche
    •  & Arthur Konnerth
  4. Department of Neurobiology, Silberman Institute of Life Sciences and Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.

    • Israel Nelken

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Contributions

M.A.B. and A.K. designed the study; M.A.B., M.K., H.A. and T.N. performed the experiments; M.A.B., M.K., H.A., H.F., I.N. and A.K. performed the analysis; M.A.B., I.N. and A.K. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marc Aurel Busche or Arthur Konnerth.

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DOI

https://doi.org/10.1038/nn.4137