The ability of synapses to change their properties in response to environmental demands (synaptic plasticity) is essential for learning and memory. Abnormalities in synaptic plasticity are involved in Alzheimer's disease and related disorders. In our continuing efforts to understand the molecular mechanisms involved in synaptic plasticity, in the contexts of aging and neurodegenerative disorders, we have made two major advances. 1) During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kappa B activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes. 2) Although ATP is reported to modulate synaptic plasticity, the mechanism of action of ATP on synaptic transmission is not fully understood. Here we show that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices. ATP rapidly increases intracellular calcium, and P2X receptor antagonists inhibit this increase in cultured dissociated neurons. These results indicate that ATP enhances LTP via activation of postsynaptic P2X receptors. In additional studies, we have found that intermittent fasting and caloric restriction ameliorate age-related learning and memory deficits in a novel transgenic mouse model of Alzheimer's disease. We also found that the antidepressant drug paroxetine was effective in suppressing amyloid pathology and preserving learning and memory ability in the same mouse model of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000317-06
Application #
7325123
Study Section
(LNS)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Stutzmann, Grace E; Mattson, Mark P (2011) Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol Rev 63:700-27
Yoon, Jeong Seon; Lee, Jong-Hwan; Son, Tae Gen et al. (2011) Pregabalin suppresses calcium-mediated proteolysis and improves stroke outcome. Neurobiol Dis 41:624-9
Conant, K; Wang, Y; Szklarczyk, A et al. (2010) Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 166:508-21
Okun, Eitan; Mattson, Mark P; Arumugam, Thiruma V (2010) Involvement of Fc receptors in disorders of the central nervous system. Neuromolecular Med 12:164-78
Jo, Dong-Gyu; Arumugam, Thiruma V; Woo, Ha-Na et al. (2010) Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease. Neurobiol Aging 31:917-25
Okun, Eitan; Griffioen, Kathleen J; Lathia, Justin D et al. (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59:278-92
Wang, Yue; Greig, Nigel H; Yu, Qian-sheng et al. (2009) Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices. Neurobiol Aging 30:1061-8
Zhang, Peisu; Pazin, Michael J; Schwartz, Catherine M et al. (2008) Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells. Curr Biol 18:1489-94
Harel, Asaff; Wu, Fangbai; Mattson, Mark P et al. (2008) Evidence for CALM in directing VAMP2 trafficking. Traffic 9:417-29
Bezprozvanny, Ilya; Mattson, Mark P (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31:454-63

Showing the most recent 10 out of 62 publications