Letter | Published:

Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice

Nature volume 526, pages 430434 (15 October 2015) | Download Citation

Abstract

Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria–fornix1,2,3, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory3,4,5. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features7. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity8,9,10,11. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

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Acknowledgements

We thank M. Xue, M. C. Weston and V. Brandt for comments on the manuscript, members of the Zoghbi laboratory for helpful discussions, and C. M. Spencer, C. T. Wotjak, F. Wei and D. Yu for technical suggestions. This work was supported by the W. M. Keck Foundation (H.Y.Z. and J.T.), the Cockrell Family Foundation, the Rett Syndrome Research Trust, Carl. C. Anderson, Sr. and Marie Jo Anderson Charitable Foundation, R01NS057819 (H.Y.Z.), and the Howard Hughes Medical Institute (H.Y.Z.), DP5OD009134 (R.C.S), R25 N070694 (A.J.P.) and in part by the Neuroconnectivity Core, Mouse Neurobehavioral Core, and Neurovisualization Core of IDDRC at Baylor College of Medicine (U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development), and the C06RR029965 grant from the National Center for Research Resources.

Author information

Affiliations

  1. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas 77030, USA

    • Shuang Hao
    • , Bin Tang
    • , Zhenyu Wu
    • , Kerstin Ure
    • , Yaling Sun
    • , Huifang Tao
    • , Yan Gao
    • , Akash J. Patel
    • , Rodney C. Samaco
    • , Huda Y. Zoghbi
    •  & Jianrong Tang
  2. Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Shuang Hao
    • , Bin Tang
    • , Zhenyu Wu
    • , Huda Y. Zoghbi
    •  & Jianrong Tang
  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Kerstin Ure
    • , Yaling Sun
    • , Huifang Tao
    • , Yan Gao
    • , Rodney C. Samaco
    •  & Huda Y. Zoghbi
  4. Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA

    • Akash J. Patel
    •  & Daniel J. Curry
  5. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Huda Y. Zoghbi
  6. Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA

    • Huda Y. Zoghbi
  7. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA

    • Huda Y. Zoghbi

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Contributions

J.T. and H.Y.Z. designed the experiments. S.H., B.T., Z.W., Y.S., H.T., Y.G., K.U. and J.T. performed the research. S.H., B.T., K.U., H.Y.Z. and J.T. analysed and interpreted the data. R.C.S., A.J.P. and D.J.C. provided comments on the manuscript. S.H., H.Y.Z. and J.T. wrote and edited the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Huda Y. Zoghbi or Jianrong Tang.

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DOI

https://doi.org/10.1038/nature15694

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