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Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease

Nature Neuroscience volume 15, pages 1422–1429 (2012)Cite this article

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Abstract

Experience-induced expression of immediate-early gene Arc (also known as Arg3.1) is known to be important for consolidation of memory. Using in vivo longitudinal multiphoton imaging, we found orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicted the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer's disease, this association was markedly disrupted in the cortex, specifically near senile plaques. Neurons in the vicinity of plaques were less likely to respond, but, paradoxically, there were stronger responses in those few neurons around plaques that did respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to and physiological consolidation of behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration.

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Figure 1: Arc-dVenus expression pattern in the visual cortex following structured light stimulation.
Figure 2: Effect of amyloid plaques on stimulus-induced Arc-dVenus expression levels.
Figure 3: Local effect of amyloid plaques on spatial distribution of Arc-dVenus–positive neurons.
Figure 4: Neurons with dystrophic neurites do not express Arc-dVenus in response to a stimulus.
Figure 5: Arc-dVenus expression in repetitive stimulation procedure.
Figure 6: Stimulus-specific Arc-dVenus expression is affected by amyloid plaque pathology.

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Change history

  • 30 August 2012

    In the version of this article initially published online, the P-value for n.s. in Figure 2e was given as 0.13. The correct value is 0.09. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank A. Muzikansky (Harvard), B. Urbanc and B. Cohen (Drexel) for their help with statistical analysis. We also thank all the members of the Hyman laboratory for their input, discussions and help with the equipment. N.R. is supported by the fellowships from the Swiss National Science Foundation and the Swiss Foundation for Grants in Biology and Medicine. This research is supported by a gift from the Gilbert fund, grants from the US National Institutes of Health (AG033670 to T.L.S.-J. and AG08487 to B.T.H.) and a grant from the Harvard NeuroDiscovery Center to R.A.B.

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Authors and Affiliations

  1. Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Nikita Rudinskiy, Jonathan M Hawkes, Tara L Spires-Jones & Bradley T Hyman

  2. Behavioral Neuroscience Program, Northeastern University, Boston, Massachusetts, USA

    Jonathan M Hawkes

  3. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Rebecca A Betensky

  4. Division of Morphological Neuroscience, Gifu University Graduate School of Medicine, Gifu, Japan

    Megumi Eguchi & Shun Yamaguchi

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Contributions

N.R., T.L.S.-J. and B.T.H. designed the experiments, analyzed the data and wrote the paper. N.R. and J.M.H. performed the experiments. M.E. and S.Y. generated Arc∷dVenus mice. R.A.B. contributed with statistical analysis of the data.

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Correspondence to Bradley T Hyman.

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The authors declare no competing financial interests.

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Rudinskiy, N., Hawkes, J., Betensky, R. et al. Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease. Nat Neurosci 15, 1422–1429 (2012). https://doi.org/10.1038/nn.3199

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