Letter

Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis

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Accepted:
Published online:

Abstract

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene1,2 and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%)3,4,5 are commonly affected with specific neuropsychological problems, including long-term and working memory deficits6,7. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2+/− mice)8 show deficits in learning and memory. Cognitive deficits in Tsc2+/− mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved5,9,10,11. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.

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References

  1. 1.

    European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).

  2. 2.

    et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808 (1997).

  3. 3.

    et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol. Med. 33, 335–344 (2003).

  4. 4.

    & The tuberous sclerosis complex. N. Engl. J. Med. 356, 92, author reply 93–94 (2007).

  5. 5.

    & The tuberous sclerosis complex proteins—a GRIPP on cognition and neurodevelopment. Trends Mol. Med. 13, 319–326 (2007).

  6. 6.

    , , , & Cognitive deficits in normally intelligent patients with tuberous sclerosis. Am. J. Med. Genet. 88, 642–646 (1999).

  7. 7.

    et al. Neuroanatomical correlates of memory deficits in tuberous sclerosis complex. Cereb. Cortex 17, 261–271 (2007).

  8. 8.

    , , , & Tsc2+/− mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J. Clin. Invest. 104, 687–695 (1999).

  9. 9.

    et al. Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis. J. Neurochem. 96, 407–413 (2006).

  10. 10.

    , , , & Impaired synaptic plasticity in a rat model of tuberous sclerosis. Eur. J. Neurosci. 23, 686–692 (2006).

  11. 11.

    , , , & Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann. Neurol. 62, 648–655 (2007).

  12. 12.

    et al. Developmental expression of the tuberous sclerosis proteins tuberin and hamartin. Acta Neuropathol. 101, 202–210 (2001).

  13. 13.

    , & Selective roles for hippocampal, prefrontal cortical and ventral striatal circuits in radial-arm maze tasks with or without a delay. J. Neurosci. 17, 1880–1890 (1997).

  14. 14.

    , & Hippocampus, space and memory. Behav. Brain Sci. 2, 313–365 (1979).

  15. 15.

    , , , & The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998).

  16. 16.

    et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur. J. Hum. Genet. 13, 731–741 (2005).

  17. 17.

    & Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. 14, R251–R258 (2005).

  18. 18.

    et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl. Acad. Sci. USA 99, 467–472 (2002).

  19. 19.

    et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11, 525–534 (2002).

  20. 20.

    & CaMKIα-Cre transgene expression and recombination patterns in the mouse brain. Genesis 26, 133–135 (2000).

  21. 21.

    , , & mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc. Natl. Acad. Sci. USA 100, 12923–12928 (2003).

  22. 22.

    , , & Genotype and psychological phenotype in tuberous sclerosis. J. Med. Genet. 41, 203–207 (2004).

  23. 23.

    et al. The relation of infantile spasms, tubers and intelligence in tuberous sclerosis complex. Arch. Dis. Child. 89, 530–533 (2004).

  24. 24.

    et al. Biological markers of intellectual disability in tuberous sclerosis. Psychol. Med. 37, 1293–1304 (2007).

  25. 25.

    & The growing role of mTOR in neuronal development and plasticity. Mol. Neurobiol. 34, 205–219 (2006).

  26. 26.

    , , , & Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8, 1727–1734 (2005).

  27. 27.

    et al. The translation repressor 4E–BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25, 9581–9590 (2005).

  28. 28.

    , & Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex–Mammalian target of rapamycin pathway. J. Neurosci. 26, 8048–8056 (2006).

  29. 29.

    & Differential translation and fragile X syndrome. Genes Brain Behav. 4, 360–384 (2005).

  30. 30.

    , , & Fragile X: translation in action. Neuropsychopharmacology 33, 84–87 (2008).

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Acknowledgements

The authors would like to thank B. Wiltgen, A. Matynia, Y.-S. Lee, R. Czajkowski, G. Ehninger and G. Kempermann for helpful comments on an earlier version of the manuscript and for valuable discussions, J.N. Crawley for helpful suggestions regarding the social interaction paradigm, M. Meredyth-Steward for editing help, I. Röder for statistical advice and R. Chen and K. Cai for technical support. This work was supported by the following grants: Deutsche Forschungsgemeinschaft EH223/2-1 to D.E., US National Institutes of Health R01-NS38480 to A.J.S., US National Institutes of Health NS24279 and Autism Speaks to V.R.

Author information

Affiliations

  1. Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, Psychology and the Brain Research Institute, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.

    • Dan Ehninger
    • , Carrie Shilyansky
    • , Yu Zhou
    • , Weidong Li
    •  & Alcino J Silva
  2. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Sangyeul Han
    •  & Vijaya Ramesh
  3. Genetics Laboratory, Division of Translational Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • David J Kwiatkowski

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Corresponding author

Correspondence to Alcino J Silva.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods