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Microtubule-associated protein tau is essential for long-term depression in the hippocampus
Kimura, Tetsuya,Whitcomb, Daniel J.,Jo, Jihoon,Regan, Philip,Piers, Thomas,Heo, Seonghoo,Brown, Christopher,Hashikawa, Tsutomu,Murayama, Miyuki,Seok, Heon,Sotiropoulos, Ioannis,Kim, Eunjoon,Collingrid The Royal Society 2014 Philosophical transactions. Biological sciences Vol.369 No.1633
<P>The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice <I>in vivo</I> and <I>in vitro</I>, an effect that was replicated by RNAi knockdown of tau <I>in vitro</I>. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.</P>
Effects of trans-10,cis-12 Conjugated Linoleic Acid on Body Composition in Genetically Obese Mice
Hur, Sun-Jin,Whitcomb, Faith,Rhee, Si-Yeon,Park, Yoo-Heon,Good, Deborah J.,Park, Yeon-Hwa The Korean Society of Food Science and Nutrition 2009 Journal of medicinal food Vol.12 No.1
Conjugated linoleic acid (CLA) has shown a number of biologically beneficial effects, including prevention of obesity. The purpose of this study was to test effects of dietary supplementation of 0.5% trans-10,cis-12 CLA in a high fat diet in neuronal basic helix-loop-helix 2 knock-out animals (N2KO), which is a unique animal model representing adult-on-set inactivity-related obesity. Eight wild-type (WT) and eight N2KO female mice were fed either 0.5% trans-10,cis-12 CLA-containing diet or control diet (with 20% soybean oil diet) for 12 weeks. Body weights, food intake, adipose tissue weights, body compositions, and blood parameters were analyzed. Overall, N2KO animals had greater body weights, food intake, adipose tissue weights, and body fat compared to WT animals. CLA supplementation decreased overall body weights and total fat, and the effect of dietary CLA on adipose tissue reduction was greater in N2KO than in WT mice. Serum leptin and triglyceride levels were reduced by CLA in both N2KO and WT animals compared to control animals, while there was no effect by CLA on serum cholesterol. The effect of CLA to lower fat mass, increase lean body mass, and lower serum leptin and triglycerides in sedentary mice supports the possibility of using CLA to prevent or alleviate ailments associated with obesity.
Effects of trans-10,cis-12 Conjugated Linoleic Acid on Body Composition in Genetically Obese Mice
Sunjin Hur,Faith Whitcomb,Siyeon Rhee,박유헌,Deborah J. Good,Yeonhwa Park 한국식품영양과학회 2009 Journal of medicinal food Vol.12 No.1
Conjugated linoleic acid (CLA) has shown a number of biologically beneficial effects, including prevention of obesity. The purpose of this study was to test effects of dietary supplementation of 0.5% trans-10,cis-12 CLA in a high fat diet in neuronal basic helix-loop-helix 2 knock-out animals (N2KO), which is a unique animal model representing adult-onset inactivity-related obesity. Eight wild-type (WT) and eight N2KO female mice were fed either 0.5% trans-10,cis-12 CLA-containing diet or control diet (with 20% soybean oil diet) for 12 weeks. Body weights, food intake, adipose tissue weights, body compositions, and blood parameters were analyzed. Overall, N2KO animals had greater body weights, food intake, adipose tissue weights, and body fat compared to WT animals. CLA supplementation decreased overall body weights and total fat, and the effect of dietary CLA on adipose tissue reduction was greater in N2KO than in WT mice. Serum leptin and triglyceride levels were reduced by CLA in both N2KO and WT animals compared to control animals, while there was no effect by CLA on serum cholesterol. The effect of CLA to lower fat mass, increase lean body mass, and lower serum leptin and triglycerides in sedentary mice supports the possibility of using CLA to prevent or alleviate ailments associated with obesity.
A pivotal role of GSK-3 in synaptic plasticity
Bradley, Clarrisa A.,Peineau, Sté,phane,Taghibiglou, Changiz,Nicolas, Celine S.,Whitcomb, Daniel J.,Bortolotto, Zuner A.,Kaang, Bong-Kiun,Cho, Kwangwook,Wang, Yu Tian,Collingridge, Graham L. Frontiers Media S.A. 2012 Frontiers in molecular neuroscience Vol.5 No.-
<P>Glycogen synthase kinase-3 (GSK-3) has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD) that is induced by the synaptic activation of N-methyl-D-aspartate receptors (NMDARs). In the present article we summarize what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarize its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders.</P>
Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95
Jo, Jihoon,Son, Gi Hoon,Winters, Bryony L,Kim, Myung Jong,Whitcomb, Daniel J,Dickinson, Bryony A,Lee, Youn-Bok,Futai, Kensuke,Amici, Mascia,Sheng, Morgan,Collingridge, Graham L,Cho, Kwangwook Nature Publishing Group, a division of Macmillan P 2010 NATURE NEUROSCIENCE Vol.13 No.10
Although muscarinic acetylcholine receptors (mAChRs) and NMDA receptors (NMDARs) are important for synaptic plasticity, learning and memory, the manner in which they interact is poorly understood. We found that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, led to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This form of LTD involved the release of Ca<SUP>2+</SUP> from IP<SUB>3</SUB>-sensitive intracellular stores and was expressed via the internalization of NMDARs. Our results suggest that the molecular mechanism involves a dynamic interaction between the neuronal calcium sensor protein hippocalcin, the clathrin adaptor molecule AP2, the postsynaptic density enriched protein PSD-95 and NMDARs. We propose that hippocalcin binds to the SH3 region of PSD-95 under basal conditions, but it translocates to the plasma membrane on sensing Ca<SUP>2+</SUP>; in doing so, it causes PSD-95 to dissociate from NMDARs, permitting AP2 to bind and initiate their dynamin-dependent endocytosis.
Tau Phosphorylation at Serine 396 Residue Is Required for Hippocampal LTD
Regan, Philip,Piers, Thomas,Yi, Jee-Hyun,Kim, Dong-Hyun,Huh, Seonghoo,Park, Se Jin,Ryu, Jong Hoon,Whitcomb, Daniel J.,Cho, Kwangwook Society for Neuroscience 2015 The Journal of neuroscience Vol.35 No.12
<P>Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD.</P>
Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity
Jang, Seil,Oh, Daeyoung,Lee, Yeunkum,Hosy, Eric,Shin, Hyewon,van Riesen, Christoph,Whitcomb, Daniel,Warburton, Julia M,Jo, Jihoon,Kim, Doyoun,Kim, Sun Gyun,Um, Seung Min,Kwon, Seok-kyu,Kim, Myoung-Hwa NATURE AMERICA 2016 NATURE NEUROSCIENCE Vol.19 No.1
<P>Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms that include trans-synaptic adhesion and recruitment of diverse synaptic proteins. We found that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule that preferentially expressed in the brain, is a dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPA glutamate receptors (AMPARs). IgSF11 required PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilized synaptic AMPARs, as determined by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice led to the suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 did not regulate the functional characteristics of AMPARs, including desensitization, deactivation or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs.</P>