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      Epigenetic regulation by G9a/GLP complex ameliorates amyloid‐beta 1‐42 induced deficits in long‐term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons

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          Summary

          Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease ( AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/ GLP complex promotes long‐term potentiation ( LTP) and its associative mechanisms such as synaptic tagging and capture ( STC). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/ GLP complex in alleviating the effects of soluble Amyloid‐β 1‐42 oligomers ( oAβ) on neuronal plasticity and associativity in the CA1 region of acute hippocampal slices from 5‐ to 7‐week‐old male Wistar rats. Our findings demonstrate that the regulation of G9a/ GLP complex by inhibiting its catalytic activity reverses the amyloid‐β oligomer‐induced deficits in late‐ LTP and STC. This is achieved by releasing the transcription repression of the brain‐derived neurotrophic factor ( Bdnf) gene. The catalytic inhibition of G9a/ GLP complex leads to the upregulation of Bdnf expression in the slices treated with oAβ. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late‐ LTP. Furthermore, the capture of BDNF by weakly activated synapses re‐establishes STC. Our findings regarding the reinstatement of functional plasticity and associativity in AD‐like conditions provide the first evidence for the role of G9a/ GLP complex in AD. We propose G9a/ GLP complex as the possible target for preventing oAβ‐induced plasticity deficits in hippocampal neurons.

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          Most cited references43

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          Long-term potentiation and memory.

          M A Lynch (2004)
          One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.
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            Synaptic tagging and long-term potentiation.

            Repeated stimulation of hippocampal neurons can induce an immediate and prolonged increase in synaptic strength that is called long-term potentiation (LTP)-the primary cellular model of memory in the mammalian brain. An early phase of LTP (lasting less than three hours) can be dissociated from late-phase LTP by using inhibitors of transcription and translation, Because protein synthesis occurs mainly in the cell body, whereas LTP is input-specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking. We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.
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              Making memories last: the synaptic tagging and capture hypothesis.

              The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.
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                Author and article information

                Contributors
                phssks@nus.edu.sg
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                30 June 2017
                October 2017
                : 16
                : 5 ( doiID: 10.1111/acel.2017.16.issue-5 )
                : 1062-1072
                Affiliations
                [ 1 ] Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Block MD9, 2 Medical Drive Singapore 117 597 Singapore
                [ 2 ] Neurobiology/Aging Program Life Sciences Institute (LSI) National University of Singapore #04‐44, 28 Medical Drive Singapore 117 456 Singapore
                [ 3 ] Institute of Innate Immunity Biomedical Centre University hospital Bonn Sigmund‐Freud‐Str. 25 Bonn 53127 Germany
                [ 4 ] Division of Cellular Neurobiology Zoological Institute Technical University Braunschweig Braunschweig Germany
                Author notes
                [*] [* ] Correspondence

                Sreedharan Sajikumar, Neurobiology/Aging Programme, Life Sciences Institute, Centre for Life Sciences, 28 Medical Drive, Singapore, 117 456. Tel.: +65 65165886; fax: +65 67773271; e‐mail:   phssks@ 123456nus.edu.sg

                Article
                ACEL12634
                10.1111/acel.12634
                5595698
                28665013
                77e6558b-ea58-446c-a8fc-dae4e2a93864
                © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 May 2017
                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 8185
                Funding
                Funded by: National Medical Research Council Collaborative Research
                Award ID: NMRCCBRG‐0041/2013
                Award ID: NMRC/CBRG/0099/2015
                Funded by: NUS‐Strategic and Aspiration Research Funds
                Funded by: President Graduate Fellowship
                Funded by: National University of Singapore
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                acel12634
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:12.09.2017

                Cell biology
                amyloid β oligomer,bdnf,epigenetics,histone lysine‐methyltransferase,long‐term potentiation,synaptic tagging/capture

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