This is the second revision of a proposal entitled """"""""Tuberous Sclerosis Complex in Memory Formation"""""""". Elucidation of the molecular events underlying the formation and storage of memory is not only relevant for understanding information processing in the brain but also for the development of therapies to treat memory disorders. Memory formation is initiated by neurotransmitters and neurotrophic factors released as a result of neuronal activity during the learning experience. Engaged neurotrophic receptors activate three key intracellular signaling cascades: Ras-Erk, PLCgamma and PI3-kinase. Although the PLCgamma and Ras- Erk pathways have been extensively examined in long-term spatial memory formation, the role of the equally important PI3K cascade in memory formation has received less attention. Recent genetic and biochemical experiments show that tuberous sclerosis protein -2 (TSC2) is phosphorylated by AKT, a key protein kinase activated by PI3K. The TSC1-TSC2 complex regulates the activity of the mammalian target for rapamycin (mTOR), which increases translation of specific mRNA through its action on ribosomal S6 kinase (S6K, also called p70s6k) and/or 4EBP1 (4E binding protein 1). The dominant role of mTOR in PI3K signaling is evident from experimental findings demonstrating that tumors caused by constitutive activation of the PI3K cascade can be targeted by rapamycin, a highly selective inhibitor for mTOR. In addition to its regulation by AKT phosphorylation, the TSC-mTOR pathway is regulated by adenosine monophosphate-activated kinase (AMPK) which acts as an energy sensor for the cell. In this proposal, we will examine in Specific Aim 1: if the TSC-mTOR pathway is activated following training and is required for spatial memory storage in the hippocampus, in Specific Aim 2: if the memory enhancing effect of glucose is in part acting through the TSC- mTOR pathway in the hippocampus, and in Specific Aim 3: if conditional tsc2 (-/-) mice have impaired spatial memory, and if these impairments can be rescued by manipulation of the mTOR pathway. The results from this study will reveal key molecular events that participate in spatial memory by investigating the activity and role of the TSC-mTOR pathway in the hippocampus. The results from these studies will provide a crucial step towards development of pharmacological and/or molecular strategies to treat memory disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurobiology of Learning and Memory Study Section (LAM)
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Mamounas, Laura
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University of Texas Health Science Center Houston
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Rozas, Natalia S; Redell, John B; McKenna 3rd, James et al. (2015) Prolonging the survival of Tsc2 conditional knockout mice by glutamine supplementation. Biochem Biophys Res Commun 457:635-9
Rozas, Natalia S; Redell, John B; Pita-Almenar, Juan D et al. (2015) Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory. Learn Mem 22:239-46
Reith, R Michelle; McKenna, James; Wu, Henry et al. (2013) Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis 51:93-103
Hylin, Michael J; Orsi, Sara A; Moore, Anthony N et al. (2013) Disruption of the perineuronal net in the hippocampus or medial prefrontal cortex impairs fear conditioning. Learn Mem 20:267-73
Way, Sharon W; Rozas, Natalia S; Wu, Henry C et al. (2012) The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum Mol Genet 21:3226-36
Pati, Shibani; Khakoo, Aarif Y; Zhao, Jing et al. (2011) Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/ýý-catenin signaling. Stem Cells Dev 20:89-101
Zhao, Jing; Redell, John B; Moore, Anthony N et al. (2011) A novel strategy to activate cytoprotective genes in the injured brain. Biochem Biophys Res Commun 407:501-6
Dash, P K; Orsi, S A; Moore, A N (2009) Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury. Neuroscience 163:1-8
Dash, Pramod K; Zhao, Jing; Orsi, Sara A et al. (2009) Sulforaphane improves cognitive function administered following traumatic brain injury. Neurosci Lett 460:103-7
Pati, Shibani; Orsi, Sara A; Moore, Anthony N et al. (2009) Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory. Brain Res 1256:85-91

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