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) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) 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 involved. 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.

Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage

“…mTOR knockout mice (mTOR −/− mice) die in utero (21,22), and brainspecific deletion of the mTORC1 up-stream regulators Tsc1 or Pten results in death within the first postnatal weeks (15,23). Thus, the study of mTORC1 signaling in adult animals has been limited.…”

“…12). Moreover, mice lacking either the mTORC1 negative regulator Tsc2 or the downstream targets 4e-bp2 and S6k1/2 exhibit altered synaptic plasticity and memory (13)(14)(15). However, several aspects of these results are controversial.…”

“…However, several aspects of these results are controversial. First, exceptionally high doses of rapamycin (150 mg/kg) are required to block contextual LTM in mice (15), whereas, in humans, blockage of mTORC1 signaling with the mTOR inhibitor everolimus appears to improve (not impair) cognition (16). Second, it was recently shown that rapamycin does not block L-LTP in the dentate gyrus in vivo (17).…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…It has been suggested that these brain malformations are dysplastic rather than neoplastic, which might explain why they are not responsive to the anti-proliferative effect of rapamycin (Bissler et al, 2008). However, pre-clinical studies in several mouse models showed improvement in neurological manifestations of TSC, such as seizures, and memory and learning deficits (Ehninger et al, 2008;Meikle et al, 2008;Zeng et al, 2008). Furthermore, reduced seizure frequencies in TSC patients have been described upon treatment with rapamycin (Franz et al, 2006;Muncy et al, 2009).…”

Dysregulation of mTOR Signaling in Neuropsychiatric Disorders: Therapeutic Implications

“…Treatment with the mTORC1 inhibitor rapamycin has shown promising results in PTEN knockout mice (Zhou et al, 2009) and TSC2 + /À mice (Ehninger et al, 2008). Thus, interventions that target mTOR signaling should be at the leading edge of future translational research in the autism field.…”