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

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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Figure 1: Tsc2+/− mice show learning deficits in three hippocampus-dependent tasks.
Figure 2: An E-LTP stimulation paradigm elicited L-LTP in Tsc2+/− mice.
Figure 3: Rapamycin reversed context discrimination and spatial learning deficits in Tsc2+/− mice.
Figure 4: Rapamycin treatment rescues lethality, reduces abnormal brain enlargement and improves neurological findings in Tsc1cc–αCaMKII-Cre mice.

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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.

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Authors and Affiliations

Authors

Contributions

D.E. and A.J.S. conceptualized the research; D.E. performed behavioral experiments and the Tsc1cc–αCaMKII-Cre study (Figs. 1, 3 and 4; Supplementary Figs. 3, 4, 6; Supplementary Table 1); D.E., C.S. and Y.Z. contributed to slice physiology experiments (Fig. 2; Supplementary Figs. 2 and 5); S.H., V.R., D.E. and W.L. contributed to western blot experiments (Supplementary Fig. 1); D.E. analyzed the data; D.J.K. provided Tsc1cc and Tsc2+/− founders for the mouse colony; D.E. and A.J.S. wrote the manuscript.

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Correspondence to Alcino J Silva.

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Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods (PDF 1963 kb)

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Ehninger, D., Han, S., Shilyansky, C. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med 14, 843–848 (2008). https://doi.org/10.1038/nm1788

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