The Akt-mTOR Pathway in Down’s Syndrome: The Potential Use of Rapamycin/Rapalogs for Treating Cognitive Deficits
Jose Antonio Troca-Marin, Juan Jose Casanas, Itziar Benito and Maria Luz Montesinos
Affiliation: Departamento de Fisiologia Medica y Biofísica, Universidad de Sevilla, Av. Sanchez-Pizjuan 4, E- 41009 Sevilla, Spain.
An increasing amount of evidence suggests that the dysregulation of the Akt-mTOR (Akt-mammalian Target
Of Rapamycin) signaling network is associated with intellectual disabilities, such as fragile X, tuberous sclerosis and
Rett’s syndrome. The Akt-mTOR pathway is involved in dendrite morphogenesis and synaptic plasticity, and it has been
shown to modulate both glutamatergic and GABAergic synaptic transmission. We have recently shown that the AktmTOR
pathway is hyperactive in the hippocampus of Ts1Cje mice, a model of Down’s syndrome, leading to increased
local dendritic translation that could interfere with synaptic plasticity. Rapamycin and rapalogs are specific inhibitors of
mTOR, and some of these inhibitors are Food and Drug Administration-approved drugs. In this review, we discuss the
molecular basis and consequences of Akt-mTOR hyperactivation in Down’s syndrome, paying close attention to
alterations in the molecular mechanisms underlying synaptic plasticity. We also analyze the pros and cons of using
rapamycin/rapalogs for the treatment of the cognitive impairments associated with this condition.
Keywords: Akt, Brain-Derived Neurotrophic Factor, Down’s syndrome, local translation, mammalian Target of Rapamycin,
rapamycin, trisomy 21, Ts1Cje.
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