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

Marc Aurel Busche*, Maja Kekuš, Helmuth Adelsberger, Takahiro Noda, Hans Förstl, Israel Nelken, Arthur Konnerth

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

145 Scopus citations


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 GABA A ergic inhibition identifies a synaptic mechanism underlying Aβ-dependent large-scale circuit dysfunction.

Original languageAmerican English
Pages (from-to)1623-1630
Number of pages8
JournalNature Neuroscience
Issue number11
StatePublished - 1 Nov 2015

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2015 Nature America, Inc.


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