title: The Akt-mTOR pathway in Down's syndrome: the potential use of rapamycin/rapalogs for treating cognitive deficits.
abstract: 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.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Troca-Marín
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Casañas
authors.forename: Itziar
authors.initials: I
authors.lastname: Benito
authors.affiliation: Departamento de Fisiologia Medica y Biofísica, Universidad de Sevilla, Av. Sanchez-Pizjuan 4, E- 41009 Sevilla, Spain. mlmontesinos@us.es.
authors.forename: María Luz
authors.initials: ML
authors.lastname: Montesinos
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus