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Synaptic Plasticity In Aging And Neurodegenerative Disorders
NATIONAL INSTITUTE ON AGING
Total Funding: $ 2,043,110
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 Alzheimers 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 Alzheimers 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 Alzheimers disease. Other experiments have shown that diabetes impairs hippocampal neurogenesis and synaptic plasticity as the result of a chronic elevation in the level of adrenal glucocorticoids. We have found that perturbed membrane sphingolipid metabolism occurs in the brain in aging, Alzheimer's disease and HIV dementia. Studies of experimental models suggest that excessive activation of sphingomyelinases result in aberrant production of ceramides and perturbed membrane excitability and synaptic plasticity. More recently, we have discovered that several different toll-like receptors (TLRs) that were previously believed to be involved only in immune responses to infection, play important roles in synaptic plasticity and learning and memory. TLRs are therefore potential targets for the development of novel therapeutic interventions for cognitive impairment and Alzheimer's disease. Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Our findings show that Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation. Presenilin 1 (PS1) mutations are responsible for many early-onset familial Alzheimer's disease (FAD) cases. While increasing evidence points to impaired synaptic plasticity as an early event in AD, PS1 mutant mice exhibit a paradoxical increase in hippocampal long-term potentiation (LTP). Among PS1 mouse models, PS1 M146V mutant knock-in mice (PS1KI) are particularly interesting in that they exhibit memory impairment in spatial tasks. Here we investigated the effects of aging on two forms of LTP in PS1KI mice, the widely-studied early phase of LTP (E-LTP) and a particular form of LTP called late-LTP (L-LTP) which requires transcription and protein synthesis. L-LTP is thought to be critical for long-term memory. We found a lower L-LTP maintenance phase in PS1KI mice compared to wild type littermates at 3 months of age. As the mice age, they exhibit impairment of both the induction and maintenance phases of LTP. When E-LTP and NMDA receptor-mediated transmission were analyzed, PS1KI mice displayed an increase at 3 months compared to wild type littermates;this difference did not persist at older ages and finally decreased at 12 months. Our These results reveal an L-LTP decrease in PS1 mutant mice at an early stage, which occurs coincidently with a paradoxical enhancement of E-LTP. The observation of a decrease in both forms of LTP during aging supports the view that PS1KI mice are a valuable model for the study of age-dependent synaptic dysfunction and cognitive decline in AD. The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. Thus, we have identified a novel an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory.
34 Resulting Publications
Marc Gleichmann; Yongqing Zhang; William H Wood; Kevin G Becker; Mohamed R Mughal; Michael J Pazin; Henriette van Praag; Tali Kobilo; Alan B Zonderman; Juan C Troncoso; et al.Neurobiology of aging 2012;33(1):205.e1-18.
Sarah J Texel; Simonetta Camandola; Bruce Ladenheim; Sarah M Rothman; Mohamed R Mughal; Erica L Unger; Jean Lud Cadet; Mark P MattsonJournal of neurochemistry 2012;120(1):125-34.
Grace E Stutzmann; Mark P MattsonPharmacological reviews 2011;63(3):700-27.
Simonetta Camandola; Mark P MattsonBiochimica et biophysica acta 2011;1813(5):965-73.
Eitan Okun; Kathleen J Griffioen; Mark P MattsonTrends in neurosciences 2011;34(5):269-81.
Sarah J Texel; Mark P MattsonAntioxidants & redox signaling 2011;14(8):1519-34.
Carola Romberg; Mark P Mattson; Mohamed R Mughal; Timothy J Bussey; Lisa M SaksidaThe Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31(9):3500-7.
Jeong Seon Yoon; Jong-Hwan Lee; Tae Gen Son; Mohamed R Mughal; Nigel H Greig; Mark P MattsonNeurobiology of disease 2011;41(3):624-9.
Dimitrios Kapogiannis; Mark P MattsonLancet neurology 2011;10(2):187-98.
Xiangru Xu; Mohamed R Mughal; F Scott Hall; Maria T G Perona; Paul J Pistell; Justin D Lathia; Srinivasulu Chigurupati; Kevin G Becker; Bruce Ladenheim; Laura E Niklason; et al.Journal of neurochemistry 2010;114(1):323-34.
Eric Norman; Roy G Cutler; Richard Flannery; Yue Wang; Mark P MattsonJournal of neurochemistry 2010;114(2):430-9.
Eitan Okun; Kathleen J Griffioen; Tae Gen Son; Jong-Hwan Lee; Nicholas J Roberts; Mohamed R Mughal; Emmette Hutchison; Aiwu Cheng; Thiruma V Arumugam; Justin D Lathia; et al.Journal of neurochemistry 2010;114(2):462-74.
Dong-Gyu Jo; Thiruma V Arumugam; Ha-Na Woo; Jong-Sung Park; Sung-Chun Tang; Mohamed Mughal; Dong-Hoon Hyun; Jun-Hyung Park; Yun-Hyung Choi; A-Ryeong Gwon; et al.Neurobiology of aging 2010;31(6):917-25.
Tinghuai Wu; Jane Tian; Roy G Cutler; Richard S Telljohann; David A Bernlohr; Mark P Mattson; James T HandaLaboratory investigation; a journal of technical methods and pathology 2010;90(6):906-14.
Eitan Okun; Mark P Mattson; Thiruma V ArumugamNeuromolecular medicine 2010;12(2):164-78.
K Conant; Y Wang; A Szklarczyk; A Dudak; M P Mattson; S T LimNeuroscience 2010;166(2):508-21.
Thiruma V Arumugam; Terry M Phillips; Aiwu Cheng; Christopher H Morrell; Mark P Mattson; Ruiqian WanAnnals of neurology 2010;67(1):41-52.
Mark P MattsonScience signaling 2010;3(114):pe10.
Dong Liu; Michael Pitta; Jong-Hwan Lee; Balmiki Ray; Debomoy K Lahiri; Katsutoshi Furukawa; Mohamed Mughal; Haiyang Jiang; Julissa Villarreal; Roy G Cutler; et al.Journal of Alzheimer's disease : JAD 2010;22(2):443-57.
Mark P MattsonExperimental gerontology 2009;44(10):625-33.
Fangbai Wu; Yasuji Matsuoka; Mark P Mattson; Pamela J YaoBiochemical and biophysical research communications 2009;385(2):247-50.
C B Lu; W Fu; X Xu; M P MattsonNeuroscience 2009;161(2):403-12.
Marc Gleichmann; Leon P Collis; Peter J S Smith; Mark P MattsonJournal of neurochemistry 2009;109(2):644-55.
Eitan Okun; Kathleen J Griffioen; Justin D Lathia; Sung-Chun Tang; Mark P Mattson; Thiruma V ArumugamBrain research reviews 2009;59(2):278-92.
Daniel A Bruestle; Roy G Cutler; Richard S Telljohann; Mark P MattsonNeuromolecular medicine 2009;11(2):58-62.
R Varma; Y Chai; J Troncoso; J Gu; H Xing; S S Stojilkovic; M P Mattson; N J HaugheyNeuromolecular medicine 2009;11(2):63-75.
Mark P Mattson; Marc Gleichmann; Aiwu ChengNeuron 2008;60(5):748-66.
Mark P MattsonAnnals of the New York Academy of Sciences 2008;1144():97-112.
Peisu Zhang; Michael J Pazin; Catherine M Schwartz; Kevin G Becker; Robert P Wersto; Caroline M Dilley; Mark P MattsonCurrent biology : CB 2008;18(19):1489-94.
Ittai Bushlin; Ronald S Petralia; Fangbai Wu; Asaff Harel; Mohamed R Mughal; Mark P Mattson; Pamela J YaoThe Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28(41):10257-71.
Alexis M Stranahan; Kim Lee; Mark P MattsonAgeing research reviews 2008;7(3):164-76.
Alexis M Stranahan; Eric D Norman; Kim Lee; Roy G Cutler; Richard S Telljohann; Josephine M Egan; Mark P MattsonHippocampus 2008;18(11):1085-8.
Rhonda L Nelson; Zhihong Guo; Veerendra Madala Halagappa; Michelle Pearson; Audrey J Gray; Yasuji Matsuoka; Martin Brown; Bronwen Martin; Titilola Iyun; Stuart Maudsley; et al.Experimental neurology 2007;205(1):166-76.
Mark P MattsonNature 2004;430(7000):631-9.
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