Letter abstract
Nature Medicine 14, 843 - 848 (2008)
Published online: 22 June 2008 | doi:10.1038/nm1788
Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis
Dan Ehninger1, Sangyeul Han2, Carrie Shilyansky1, Yu Zhou1, Weidong Li1, David J Kwiatkowski3, Vijaya Ramesh2 & Alcino J Silva1
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.
- 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.
- Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
- Genetics Laboratory, Division of Translational Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA.
Correspondence to: Alcino J Silva1 e-mail: silvaa@mednet.ucla.edu
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