Letter | Published:

Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann. Neurol. 68, 521–534 (2010)

  2. 2.

    et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann. Neurol. 63, 119–123 (2008)

  3. 3.

    , & Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes. Proc. Natl Acad. Sci. USA 107, 7054–7059 (2010)

  4. 4.

    & Lesions of the fornix but not the entorhinal or perirhinal cortex interfere with contextual fear conditioning. J. Neurosci. 15, 5308–5315 (1995)

  5. 5.

    & Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats. Neurobiol. Learn. Mem. 67, 142–149 (1997)

  6. 6.

    et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999)

  7. 7.

    & The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)

  8. 8.

    , , , & Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)

  9. 9.

    et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010)

  10. 10.

    et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006)

  11. 11.

    et al. Female Mecp2+/− mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum. Mol. Genet. 22, 96–109 (2013)

  12. 12.

    et al. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch. Neurol. 66, 781–785 (2009)

  13. 13.

    et al. Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Neuropharmacology 64, 414–423 (2013)

  14. 14.

    et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N. Engl. J. Med. 366, 502–510 (2012)

  15. 15.

    & Commissural projection to the amygdala through the fimbria fornix system in the cat. Exp. Brain Res. 27, 61–70 (1977)

  16. 16.

    , , & Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982)

  17. 17.

    et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neurosci. 4, 289–296 (2001)

  18. 18.

    , & Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999)

  19. 19.

    et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001)

  20. 20.

    Dynamic learning and memory, synaptic plasticity and neurogenesis: an update. Front. Behav. Neurosci. 8, 106 (2014)

  21. 21.

    , , , & The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J. Neurosurg. 108, 132–138 (2008)

  22. 22.

    , , & Neurogenic hippocampal targets of deep brain stimulation. J. Comp. Neurol. 519, 6–20 (2011)

  23. 23.

    et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J. Neurosci. 31, 13469–13484 (2011)

  24. 24.

    , , , & Altered neurochemical markers in Rett’s syndrome. Neurology 41, 1753–1756 (1991)

  25. 25.

    & Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron 52, 197–204 (2006)

  26. 26.

    et al. Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease. Mov. Disord. 22, 2126–2129 (2007)

  27. 27.

    , , , & Pallidal deep-brain stimulation associated with complete remission of self-injurious behaviors in a patient with Lesch–Nyhan syndrome: a case report. J. Child Neurol. 27, 117–120 (2012)

  28. 28.

    , , , & Deep-brain stimulation for aggressive and disruptive behavior. World Neurosurg. 80, S29.e11–s29.e14 (2013)

  29. 29.

    & LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004)

  30. 30.

    & Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008)

  31. 31.

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

  32. 32.

    , & Deep brain stimulation for cognitive disorders. Handb. Clin. Neurol. 116, 307–311 (2013)

  33. 33.

    , & Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res. 661, 25–34 (1994)

  34. 34.

    & Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J. Neurosci. 21, 1720–1726 (2001)

  35. 35.

    et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav. Brain Res. 176, 4–20 (2007)

  36. 36.

    et al. Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav. Brain Res. 243, 79–90 (2013)

  37. 37.

    & Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav. Brain Res. 136, 489–501 (2002)

  38. 38.

    et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243–254 (2002)

  39. 39.

    et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004)

  40. 40.

    et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002)

  41. 41.

    , , , & Induction and duration of long-term potentiation in the hippocampus of the freely moving mouse. J. Neurosci. Methods 75, 75–80 (1997)

  42. 42.

    & Dopamine enables in vivo synaptic plasticity associated with the addictive drug nicotine. Neuron 63, 673–682 (2009)

  43. 43.

    et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675–686 (2001)

  44. 44.

    , & Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur. J. Neurosci. 36, 3521–3530 (2012)

  45. 45.

    , , & Learning to learn: theta oscillations predict new learning, which enhances related learning and neurogenesis. PLoS ONE 7, e31375 (2012)

  46. 46.

    NMDA receptor blockers prevents the facilitatory effects of post-training intra-dorsal hippocampal NMDA and physostigmine on memory retention of passive avoidance learning in rats. Behav. Brain Res. 169, 120–127 (2006)

  47. 47.

    , , , & Cholinergic mechanism involved in the nociceptive modulation of dentate gyrus. Biochem. Biophys. Res. Commun. 379, 975–979 (2009)

Download references


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


  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


  1. Search for Shuang Hao in:

  2. Search for Bin Tang in:

  3. Search for Zhenyu Wu in:

  4. Search for Kerstin Ure in:

  5. Search for Yaling Sun in:

  6. Search for Huifang Tao in:

  7. Search for Yan Gao in:

  8. Search for Akash J. Patel in:

  9. Search for Daniel J. Curry in:

  10. Search for Rodney C. Samaco in:

  11. Search for Huda Y. Zoghbi in:

  12. Search for Jianrong Tang in:


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.

Extended data

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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