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Long-term depression in the CNS
Collingridge, Graham L.,Peineau, Stephane,Howland, John G.,Wang, Yu Tian Nature Publishing Group, a division of Macmillan P 2010 Nature reviews. Neuroscience Vol.11 No.7
<P>Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-d-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.</P>
Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain
Bliss, Tim V. P.,Collingridge, Graham L.,Kaang, Bong-Kiun,Zhuo, Min Nature Publishing Group, a division of Macmillan P 2016 Nature reviews. Neuroscience Vol.17 No.8
<P>The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.</P>
Shank mutant mice as an animal model of autism
Yoo, Juyoun,Bakes, Joseph,Bradley, Clarrisa,Collingridge, Graham L.,Kaang, Bong-Kiun Royal Society 2014 Philosophical transactions. Biological sciences Vol.369 No.1633
<P>In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.</P>
Erasing injury-related cortical synaptic potentiation as a new treatment for chronic pain.
Li, Xiang-Yao,Ko, Hyoung-Gon,Chen, Tao,Collingridge, Graham L,Kaang, Bong-Kiun,Zhuo, Min Springer 2011 Journal of molecular medicine Vol.89 No.9
<P>Synaptic plasticity in the spinal cord and the cortex is believed to be important for the amplification of painful information in chronic pain conditions. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes, such as through the study of long-term potentiation in these structures, provides potential novel targets for designing new medicine for chronic pain. Recent studies using integrative neurobiological approaches demonstrate that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the anterior cingulate cortex (ACC), and inhibiting PKMζ by ζ-pseudosubstrate inhibitory peptide produces analgesic effects in animal models of chronic pain. We propose that targeting PKMζ, or its up- or downstream signaling proteins, in the ACC may provide novel clinical treatment for chronic pain.</P>
Targeting synaptic dysfunction in Alzheimer's disease therapy.
Nistic?, Robert,Pignatelli, Marco,Piccinin, Sonia,Mercuri, Nicola B,Collingridge, Graham Humana Press 2012 Molecular neurobiology Vol.46 No.3
<P>In the past years, major efforts have been made to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been translated into extensive experimental approaches aimed at slowing down or halting disease progression. Advances in transgenic (Tg) technologies allowed the engineering of different mouse models of AD recapitulating a range of AD-like features. These Tg models provided excellent opportunities to analyze the bases for the temporal evolution of the disease. Several lines of evidence point to synaptic dysfunction as a cause of AD and that synapse loss is a pathological correlate associated with cognitive decline. Therefore, the phenotypic characterization of these animals has included electrophysiological studies to analyze hippocampal synaptic transmission and long-term potentiation, a widely recognized cellular model for learning and memory. Transgenic mice, along with non-Tg models derived mainly from exogenous application of Aβ, have also been useful experimental tools to test the various therapeutic approaches. As a result, numerous pharmacological interventions have been reported to attenuate synaptic dysfunction and improve behavior in the different AD models. To date, however, very few of these findings have resulted in target validation or successful translation into disease-modifying compounds in humans. Here, we will briefly review the synaptic alterations across the different animal models and we will recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. Finally, we will highlight intrinsic limitations in the use of experimental systems and related challenges in translating preclinical studies into human clinical trials.</P>
Park, Pojeong,Sanderson, Thomas M.,Amici, Mascia,Choi, Sun-Lim,Bortolotto, Zuner A.,Zhuo, Min,Kaang, Bong-Kiun,Collingridge, Graham L. Society for Neuroscience 2016 The Journal of neuroscience Vol.36 No.2
<P>Two forms of NM DA receptor (NMDAR)-dependent long-term potentiation (LIP) at hippocampal CAI synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LIP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CAI synapses. We find that LIP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LIP.</P>
Park, Pojeong,Volianskis, Arturas,Sanderson, Thomas M.,Bortolotto, Zuner A.,Jane, David E.,Zhuo, Min,Kaang, Bong-Kiun,Collingridge, Graham L. The Royal Society 2014 Philosophical transactions. Biological sciences Vol.369 No.1633
<P><I>N</I>-methyl-<SMALL>D</SMALL>-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.</P>
Park, Pojeong,Volianskis, Arturas,Sanderson, Thomas M.,Bortolotto, Zuner A.,Jane, David E.,Zhuo, Min,Kaang, Bong-Kiun,Collingridge, Graham L. Royal Society of London 2014 Philosophical transactions. Biological sciences Vol.369 No.1633
N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.