Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice


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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Forniceal DBS restores contextual fear memory in RTT mice.
Figure 2: Forniceal DBS rescues spatial learning and memory in RTT mice.
Figure 3: Forniceal DBS rescues hippocampal synaptic plasticity in freely moving RTT mice.
Figure 4: Forniceal DBS stimulates hippocampal neurogenesis in wild-type and RTT mice.


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

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  3. Shirvalkar, P. R., Rapp, P. R. & Shapiro, M. L. Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes. Proc. Natl Acad. Sci. USA 107, 7054–7059 (2010)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  5. Maren, S. & Fanselow, M. S. 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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  7. Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)

    CAS  Article  Google Scholar 

  8. Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  11. Samaco, R. C. 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)

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  13. Whittle, N. 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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  15. Gary-Bobo, E. & Bonvallet, M. Commissural projection to the amygdala through the fimbria fornix system in the cat. Exp. Brain Res. 27, 61–70 (1977)

    CAS  Article  Google Scholar 

  16. Morris, R. G., Garrud, P., Rawlins, J. N. & O’Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982)

    ADS  CAS  Article  Google Scholar 

  17. Jones, M. W. 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)

    CAS  Article  Google Scholar 

  18. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  21. Toda, H., Hamani, C., Fawcett, A. P., Hutchison, W. D. & Lozano, A. M. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J. Neurosurg. 108, 132–138 (2008)

    Article  Google Scholar 

  22. Encinas, J. M., Hamani, C., Lozano, A. M. & Enikolopov, G. Neurogenic hippocampal targets of deep brain stimulation. J. Comp. Neurol. 519, 6–20 (2011)

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  24. Wenk, G. L., Naidu, S., Casanova, M. F., Kitt, C. A. & Moser, H. Altered neurochemical markers in Rett’s syndrome. Neurology 41, 1753–1756 (1991)

    CAS  Article  Google Scholar 

  25. Wichmann, T. & Delong, M. R. Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron 52, 197–204 (2006)

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  27. Deon, L. L., Kalichman, M. A., Booth, C. L., Slavin, K. V. & Gaebler-Spira, D. J. 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)

    Article  Google Scholar 

  28. Franzini, A., Broggi, G., Cordella, R., Dones, I. & Messina, G. Deep-brain stimulation for aggressive and disruptive behavior. World Neurosurg. 80, S29.e11–s29.e14 (2013)

    Article  Google Scholar 

  29. Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004)

    CAS  Article  Google Scholar 

  30. Ramocki, M. B. & Zoghbi, H. Y. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008)

    ADS  CAS  Article  Google Scholar 

  31. Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, 2001)

    Google Scholar 

  32. Laxton, A. W., Lipsman, N. & Lozano, A. M. Deep brain stimulation for cognitive disorders. Handb. Clin. Neurol. 116, 307–311 (2013)

    Article  Google Scholar 

  33. Maren, S., De Oca, B. & Fanselow, M. S. 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)

    CAS  Article  Google Scholar 

  34. Corcoran, K. A. & Maren, S. Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J. Neurosci. 21, 1720–1726 (2001)

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  41. Davis, S., Bliss, T. V., Dutrieux, G., Laroche, S. & Errington, M. L. Induction and duration of long-term potentiation in the hippocampus of the freely moving mouse. J. Neurosci. Methods 75, 75–80 (1997)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  44. Nokia, M. S., Anderson, M. L. & Shors, T. J. Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. Eur. J. Neurosci. 36, 3521–3530 (2012)

    Article  Google Scholar 

  45. Nokia, M. S., Sisti, H. M., Choksi, M. R. & Shors, T. J. Learning to learn: theta oscillations predict new learning, which enhances related learning and neurogenesis. PLoS ONE 7, e31375 (2012)

    ADS  CAS  Article  Google Scholar 

  46. Jafari-Sabet, M. 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)

    CAS  Article  Google Scholar 

  47. Jiao, R., Yang, C., Zhang, Y., Xu, M. & Yang, X. Cholinergic mechanism involved in the nociceptive modulation of dentate gyrus. Biochem. Biophys. Res. Commun. 379, 975–979 (2009)

    CAS  Article  Google Scholar 

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

Authors and Affiliations



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.

Corresponding authors

Correspondence to Huda Y. Zoghbi or Jianrong Tang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Timeline of forniceal DBS tests in RTT and wild-type mice.

Extended Data Figure 2 Fear memory in RTT mice and wild-type control animals.

All mice were trained with tone–foot-shock pairings on day 0. Memory retention was tested 3 h, 1 day, 3 day, and 7 day after training. a, b, Impaired fear memory in RTT mice (n = 20) compared to wild-type (WT) littermates (n = 20). These animals were implanted with electrodes but did not receive DBS or sham treatment. A significant main effect of genotype was observed (two-way repeated-measures ANOVA followed by Tukey’s post hoc test: context, F1,38 = 15.32, P < 0.001; cue, F1,38 = 20.70, P < 0.001). *P < 0.05; **P < 0.01; ***P < 0.001 versus wild type. c, d, Cued fear memory in RTT mice (n = 20) and wild-type littermates (n = 20) that were implanted with electrodes but without DBS or sham treatment. During the retention test, freezing in the tone phase (T) was significantly more than in the no tone phase (NT) across all the test time points in both wild-type (c) and RTT mice (d). eh, Retrieval of cue fear memory in DBS- or sham-treated RTT and wild-type mice. During the cued memory test, all four groups of animals actively responded to the tone presentation (WT-sham, n = 21; WT-DBS, n = 21; RTT-sham, n = 14; RTT-DBS, n = 17). There was a significant increase of freezing time in the tone phase (T) compared to the no-tone phase (NT) at each of the test time points over all the groups. *P < 0.05, **P < 0.01, ***P < 0.001 (two-tailed paired t-test). All data are presented as mean ± s.e.m.

Extended Data Figure 3 Increased handling, but not forniceal DBS, increased locomotor activity and decreased the anxiety level in RTT and wild-type mice.

a, There was no difference among the four DBS/sham-treated groups in the total distance travelled in the open-field test (WT-sham, n = 20; WT-DBS, n = 20; RTT-sham, n = 17; RTT-DBS, n = 18; genotype, F1,71 = 1.13, P = 0.292; treatment, F1,71 = 0.13, P = 0.724; genotype × treatment, F1,71 = 0.063, P = 0.803). RTT and wild-type mice that received DBS/sham treatment travelled longer distances than RTT (n = 20) and wild-type (n = 20) animals that were implanted with electrodes but did not experience DBS/sham procedures, respectively. b, During the open-field test, there was no difference in the centre:total distance ratio among the four DBS groups (genotype, F1,71 = 1.22, P = 0.273; treatment, F1,71 = 0.0079, P = 0.93; genotype × treatment, F1,71 = 0.081, P = 0.777). Both RTT and wild-type mice that received DBS/sham treatment travelled more in the centre area compared to implanted RTT and wild-type animals that did not recieve DBS/sham procedures. c, In the light/dark test there was no difference in the amount of time spent in the light compartment among the four chronically treated groups (n = 12 per group; two-way ANOVA: genotype, F1,44 = 1.83, P = 0.183; treatment, F1,44 = 0.057, P = 0.813; genotype × treatment, F1,44 = 0.33, P = 0.567). Both RTT and wild-type mice that received DBS/sham treatment spent more time in the light compartment than implanted RTT (n = 15) and wild-type (n = 14) animals that did not receive DBS/sham procedures. *P < 0.05,0 **P < 0.01, ***P < 0.001 (two-tailed t-test). All data are presented as mean ± s.e.m.

Extended Data Figure 4 Forniceal DBS did not alter the pain threshold, motor function or social behaviour in RTT or wild-type mice.

a, There was no group difference in foot shock threshold intensities to evoke flinch, vocalization or jumping (WT-sham, n = 14; WT-DBS, n = 14; RTT-sham, n = 11; RTT-DBS, n = 12; two-way ANOVA, no significant main effect of genotype, treatment, or genotype × treatment interaction, P > 0.05). b, In a rotarod test (n = 12 mice per group), latency to fall increased over trials but there was no difference among the four groups (two-way repeated measures ANOVA: group, F3,44 = 1.68, P = 0.184; trial, F7,308 = 34.26, P < 0.001; group × trial interaction, F21,308 = 1.22, P = 0.230). c, RTT mice showed decreased latency to fall in the wire-hang test compared to wild-type animals, but there was no difference between DBS- and sham-treated groups for either RTT or wild-type mice (n = 12 per group; two-way ANOVA: genotype, F1,44 = 10.41, P = 0.002; treatment, F1,44 = 0.33, P = 0.566; genotype × treatment interaction, F1,44 = 0.75, P = 0.392). d, RTT mice showed a decreased latency to fall in the dowel test compared to wild-type animals, but there was no difference between DBS- and sham-treated groups for either genotype (n = 12 per group; genotype, F1,44 = 23.63, P < 0.001; treatment, F1,44 = 0.0018, P = 0.966; genotype × treatment interaction, F1,44 = 0.83, P = 0.367). e, f, In the three chamber test, all four groups of animals (n = 12 per group) showed a clear preference for the partner mice compared to the object (e). Two-way ANOVA revealed a significant genotype main effect of the interaction time with the partner mice (F1,44 = 4.56, P = 0.038), indicating altered social behaviour in RTT mice (P = 0.063, RTT-sham versus WT-sham, Tukey’s post hoc). However, DBS did not change the interaction time with the partners (treatment, F1,44 = 0.28, P = 0.597; genotype × treatment interaction, F1,44 = 0.31, P = 0.579) or the object (treatment, F1,44 = 2.64, P = 0.111; genotype × treatment interaction, F1,44 = 0.015, P = 0.905) (f). **P < 0.01, ***P < 0.001 (Tukey’s post hoc in c, d; two-tailed paired t-test in e). All data are presented as mean ± s.e.m.

Extended Data Figure 5 Forniceal DBS did not alter the body weight, visual or sensorimotor skills in RTT or wild-type mice.

a, All four groups (n = 12 mice per group) showed changes in body weight over time. Two-way repeated measure ANOVA revealed a significant main effect of group (F3,44 = 6.73, P < 0.001) and age (F4,176 = 89.32, P < 0.001). Tukey’s post hoc showed that sham-treated RTT mice were significantly heavier than sham-treated wild-type mice (P = 0.015), but there was no difference in body weight between sham-treated and DBS-treated wild-type mice (P = 0.861) or between sham-treated and DBS-treated RTT mice (P = 0.099). b, Comparison of body weight at the age of 23 weeks among the four groups (two-way ANOVA: genotype, F1,44 = 10.06, P = 0.003; treatment: F1,44 = 1.93, P = 0.172). ce, Swimming test in the water maze task with a flagged platform (n = 18 mice per group). Sham-treated RTT mice did not have different escape latencies than sham-treated wild-type controls (c, two-way repeated-measures ANOVA: genotype, F1,34 = 1.73, P = 0.197; genotype × treatment interaction, F1,34 = 0.133, P = 0.718). DBS did not change the escape latencies in either wild-type controls (d; treatment, F1,34 = 0.44, P = 0.513; treatment × day interaction, F1,34 = 1.24, P = 0.273) or RTT mice (e, treatment, F1,34 = 2.36, P = 0.134; treatment × day interaction, F1,34 = 0.41, P = 0.524). *P < 0.05; n.s., not significant (Tukey’s post hoc). All data are presented as mean ± s.e.m.

Extended Data Figure 6 Effect of forniceal DBS on hippocampal electrophysiological signatures.

a, Representative traces of LFPs recorded in the dentate gyrus 1 day before and 3 weeks after DBS/sham treatment. There were no electrographic seizure spikes in any of the four groups of mice after DBS/sham treatment. Scale bars: 10 s, 1 mV. b, Input–output (I/O) curves of the evoked responses of the perforant path recorded in the dentate gyrus in DBS/sham-treated mice. For each of the four groups, I/O curves were generated 1 day before and 3 weeks after forniceal DBS. All data points were normalized to the maximum value of the population spike amplitude before DBS/sham and the abscissa represents the seven increments used in each mouse. The I/O relationship was not altered by DBS in sham-treated wild-type mice (WT-sham; n = 5, F1,4 = 0.062, P = 0.818), DBS-treated wild-type mice (WT-DBS; n = 4, F1,3 = 0.036, P = 0.861), or sham-treated RTT mice (RTT-sham; n = 5, F1,4 = 0.018, P = 0.901). DBS reduced the amplitude of the evoked population spikes from the baseline test in DBS-treated RTT mice (RTT-DBS; n = 5, F1,4 = 6.73, P = 0.060). *P < 0.05 (Tukey’s post hoc). All data are presented as mean ± s.e.m.

Extended Data Figure 7 Unilateral forniceal DBS induces neuronal activity and stimulates neurogenesis bilaterally in the dentate gyrus.

a, Representative images showing that expression of the Fos gene was increased following forniceal DBS in wild-type and RTT mice compared to their sham controls, respectively (percentage of ipsilateral c-Fos-positive cells over the dentate granule cells: WT-sham, 0.26 ± 0.04%; WT-DBS, 34.52 ± 4.62%; RTT-sham, 0.30 ± 0.05%; RTT-DBS, 32.55 ± 3.74%). b, Representative images showing that there were more BrdU+ (green), DCX+ (red), and merged (yellow) cells in the dentate gyrus in forniceal DBS-treated wild-type and RTT mice than in their respective sham controls. Scale bar, 100 µm. Con, contralateral; Ips, ipsilateral.

Extended Data Figure 8 The cholinergic antagonist atropine did not alter forniceal DBS-induced enhancement of fear memory.

a, Placement of guide cannula and recording electrode into the dorsal hippocampus. b, Hippocampal infusion of 1.0 µg atropine did not change the amplitudes of the evoked potentials of the FFx recorded in the dentate gyrus in both RTT and wild-type mice. There was no difference of the population spike amplitudes before or after atropine infusion in both RTT mice (n = 5; one-way ANOVA, F9,36 = 0.69, P = 0.715) and wild-type controls (n = 3; F9,18 = 0.99, P = 0.485). c, Representative hippocampal EEG traces before and after vehicle (V) or atropine (A) infusion. Scale bars: 0.5 s, 0.2 mV. d, RTT mice (n = 17) showed less spontaneous hippocampal theta activity than wild-type animals (n = 20) (**P < 0.01, two-tailed t-test). e, Hippocampal infusion of atropine, but not vehicle, reduced hippocampal theta oscillation in both RTT and wild-type mice compared to their pre-infusion baselines (WT-V, n = 9; WT-A, n = 11; RTT-V, n = 8; RTT-A, n = 9; *P < 0.05, two-tailed paired t-test; n.s., not significant). f, Hippocampal microinfusion of atropine before fear conditioning training did not alter fear memory in forniceal DBS treated RTT mice or wild-type controls. Mice in all four groups (WT-V, n = 10; WT-A, n = 11; RTT-V, n = 12; RTT-A, n = 13) experienced 2 weeks of forniceal DBS that was finished 3 weeks before fear conditioning training. Atropine or vehicle was bilaterally infused into the dorsal hippocampus before training. Memory retention was tested 24 h after training. Two-way ANOVA revealed a significant main effect of genotype (F1,42 = 10.27, P = 0.003), but there was no difference between atropine- and vehicle-treated mice (treatment, F1,42 = 0.34, P = 0.562; genotype × treatment interaction, F1,42 = 0.069, P = 0.794). Atropine did not change cued fear memory, either: two-way ANOVA revealed no difference between genotypes (F1,42 = 2.99, P = 0.091) or between atropine- and vehicle-treated mice (treatment, F1,42 = 0.046, P = 0.831; genotype × treatment interaction, F1,42 = 0.154, P = 0.697). *P < 0.05; n.s., not significant (Tukey’s post hoc). g, Intra-hippocampal atropine infusion alone did not change the basal level of freezing in the contextual test environment in either wild-type or RTT mice. There was no difference between vehicle- (n = 9) or atropine-treated (n = 6) mice (P > 0.05, two-tailed t-test). h, Schematic representation of the dorsal hippocampus at seven rostral-caudal planes (according to ref. 31) for the microinfusion sites in DBS-treatment experiments. The numbers on the left represent the posterior coordinate from the bregma. All data are presented as mean ± s.e.m.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hao, S., Tang, B., Wu, Z. et al. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature 526, 430–434 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

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.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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