The Experts below are selected from a list of 1278 Experts worldwide ranked by ideXlab platform
Sreedharan Sajikumar - One of the best experts on this subject based on the ideXlab platform.
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Group III metabotropic glutamate receptors gate long-term potentiation and Synaptic Tagging/capture in rat hippocampal area CA2
eLife, 2020Co-Authors: Ananya Dasgupta, Nimmi Baby, Thomas Behnisch, Yu Jia Lim, Krishna Kumar, Ka Lam Karen Pang, Amrita Benoy, Sreedharan SajikumarAbstract:Metabotropic glutamate receptors (mGluRs) play an important role in Synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic glutamate receptors are known to down-regulate cAMP-dependent signaling pathways via the activation of Gi/o proteins. Here, we provide evidence that inhibition of group III mGluRs by specific antagonists permits an NMDA receptor- and protein synthesis-dependent long-lasting Synaptic potentiation in the apparently long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. Moreover, long-lasting potentiation of these synapses transforms a transient Synaptic potentiation of the entorhinal cortical (EC)-CA2 synapses into a stable long-lasting LTP, in accordance with the Synaptic Tagging/capture hypothesis (STC). Furthermore, this study also sheds light on the role of ERK/MAPK protein signaling and the downregulation of STEP protein in the group III mGluR inhibition-mediated plasticity in the hippocampal CA2 region, identifying them as critical molecular players. Thus, the regulation of group III mGluRs provides a conducive environment for the SC-CA2 synapses to respond to events that could lead to activity-dependent Synaptic plasticity.
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group iii metabotropic glutamate receptors gate long term potentiation and Synaptic Tagging capture in rat hippocampal area ca2
eLife, 2020Co-Authors: Ananya Dasgupta, Nimmi Baby, Thomas Behnisch, Yu Jia Lim, Krishna Kumar, Ka Lam Karen Pang, Amrita Benoy, Sreedharan SajikumarAbstract:Metabotropic glutamate receptors (mGluRs) play an important role in Synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic glutamate receptors are known to down-regulate cAMP-dependent signaling pathways via the activation of Gi/o proteins. Here, we provide evidence that inhibition of group III mGluRs by specific antagonists permits an NMDA receptor- and protein synthesis-dependent long-lasting Synaptic potentiation in the apparently long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. Moreover, long-lasting potentiation of these synapses transforms a transient Synaptic potentiation of the entorhinal cortical (EC)-CA2 synapses into a stable long-lasting LTP, in accordance with the Synaptic Tagging/capture hypothesis (STC). Furthermore, this study also sheds light on the role of ERK/MAPK protein signaling and the downregulation of STEP protein in the group III mGluR inhibition-mediated plasticity in the hippocampal CA2 region, identifying them as critical molecular players. Thus, the regulation of group III mGluRs provides a conducive environment for the SC-CA2 synapses to respond to events that could lead to activity-dependent Synaptic plasticity.
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microrna 134 5p inhibition rescues long term plasticity and Synaptic Tagging capture in an aβ 1 42 induced model of alzheimer s disease
Aging Cell, 2020Co-Authors: Nimmi Baby, S. Thameem Dheen, Nithyakalyani Alagappan, Sreedharan SajikumarAbstract:Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as Synaptic Tagging and capture (STC) were impaired in Aβ (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aβ (1-42)-treated AD hippocampus. Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD. In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.
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MicroRNA-134-5p inhibition rescues long-term plasticity and Synaptic Tagging/capture in an Aβ(1-42)-induced model of Alzheimer's disease.
Aging Cell, 2019Co-Authors: Nimmi Baby, S. Thameem Dheen, Nithyakalyani Alagappan, Sreedharan SajikumarAbstract:Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as Synaptic Tagging and capture (STC) were impaired in Aβ (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aβ (1-42)-treated AD hippocampus. Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD. In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.
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The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation.
The Journal of Neuroscience, 2019Co-Authors: Lik-wei Wong, Jason Y. Tann, Carlos F. Ibáñez, Sreedharan SajikumarAbstract:Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired Synaptic Tagging and capture and behavioral Tagging, two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75NTR) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75NTR expression and its interaction with phosphodiesterase. p75NTR deletion preserved hippocampal structural and functional plasticity by preventing SD-mediated effects on hippocampal cAMP-CREB-BDNF, cAMP-PKA-LIMK1-cofilin, and RhoA-ROCK2 pathways. Our study identifies p75NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.SIGNIFICANCE STATEMENT The lack of sufficient sleep is a major health concern in today's world. Sleep deprivation (SD) affects cognitive functions such as memory. We have investigated how associative memory mechanisms, Synaptic Tagging and capture (STC), was impaired in SD mice at cellular and behavioral level. Interestingly, mutant male mice that lacked the p75 neurotrophin receptor (p75NTR) were seen to be resistant to the SD-induced impairments in hippocampal Synaptic plasticity and STC. Additionally, we elucidated the molecular pathways responsible for this rescue of plasticity in the mutant mice. Our study has thus identified p75NTR as a promising target to limit the cognitive deficits associated with SD.
Richard G. M. Morris - One of the best experts on this subject based on the ideXlab platform.
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State based model of long-term potentiation and Synaptic Tagging and capture
2016Co-Authors: Richard G. M. Morris, Adam B Barrett, See Profile, Guy Billings, Mark C W Van Rossum, Guy O. BillingsAbstract:Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in Synaptic Tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of Synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point fo
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Differential Role of CaMK in Synaptic Tagging and Capture
Synaptic Tagging and Capture, 2014Co-Authors: Roger L. Redondo, Richard G. M. MorrisAbstract:Long-term potentiation (LTP) of Synaptic connectivity is theorized to be a physiological correlate of memory formation. Changes in Synaptic strength, as well as their maintenance, depend on a network of chemical interactions that occur both locally at the synapse and across the dendrites, axons, and nucleus of the neuron. The Calmodulin Kinase (CaMK) family can be divided into CaMKI/IV and CaMKII subfamilies among others, all with central roles in Synaptic plasticity. The question that we address in this chapter is whether the necessary roles of particular CaM Kinases in LTP are restricted to the synthesis of plasticity-related products or to the local phosphorylation of Synaptic proteins. We use analytically powerful three-pathway protocols and kinase-specific drugs to dissociate the distinct roles of the CaMK pathways in LTP.
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Synaptic Tagging and capture in the living rat
Nature Communications, 2012Co-Authors: Katherine L. Shires, Richard G. M. Morris, B. M. Da Silva, J. P. Hawthorne, Stephen J. MartinAbstract:Synaptic Tagging and capture describes the in vitro protein synthesis-dependent neuronal process where short-lasting forms of response potentiation are stabilised into long-lasting forms. Shires and colleagues find that this phenomenon also occurs in vivo in intact, living animals.
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Making memories last: The Synaptic Tagging and capture hypothesis
Nature Reviews Neuroscience, 2011Co-Authors: Roger L. Redondo, Richard G. M. MorrisAbstract: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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relevance of Synaptic Tagging and capture to the persistence of long term potentiation and everyday spatial memory
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Szuhan Wang, Roger L. Redondo, Richard G. M. MorrisAbstract:Abstract Memory for inconsequential events fades, unless these happen before or after other novel or surprising events. However, our understanding of the neurobiological mechanisms of novelty-enhanced memory persistence is mainly restricted to aversive or fear-associated memories. We now outline an “everyday appetitive” behavioral model to examine whether and how unrelated novelty facilitates the persistence of spatial memory coupled to parallel electrophysiological studies of the persistence of long-term potentiation (LTP). Across successive days, rats were given one trial per day to find food in different places and later had to recall that day's location. This task is both hippocampus and NMDA receptor dependent. First, encoding with low reward induced place memory that decayed over 24 h; in parallel, weak tetanization of CA1 synapses in brain slices induced early-LTP fading to baseline. Second, novelty exploration scheduled 30 min after this weak encoding resulted in persistent place memory; similarly, strong tetanization—analogous to novelty—both induced late-LTP and rescued early- into late-LTP on an independent but convergent pathway. Third, hippocampal dopamine D1/D5 receptor blockade or protein synthesis inhibition within 15 min of exploration prevented persistent place memory and blocked late-LTP. Fourth, symmetrically, when spatial memory was encoded using strong reward, this memory persisted for 24 h unless encoding occurred under hippocampal D1/D5 receptor blockade. Novelty exploration before this encoding rescued the drug-induced memory impairment. Parallel effects were observed in LTP. These findings can be explained by the Synaptic Tagging and capture hypothesis.
Julietta Uta Frey - One of the best experts on this subject based on the ideXlab platform.
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Protein degradation by the proteasome is required for Synaptic Tagging and the heteroSynaptic stabilization of hippocampal late-phase long-term potentiation.
Neuroscience, 2010Co-Authors: F. Cai, Julietta Uta Frey, Pietro Paolo Sanna, Thomas BehnischAbstract:Activity-dependent regulation of Synaptic efficacy is believed to underlie learning and memory formation. Here we show that protein degradation by the proteasome is required for the induction of the protein synthesis-dependent late-phase of long-term potentiation (late-LTP) but not for its maintenance. Proteasome activity was also key to the polarity of heteroSynaptic interactions between synapses expressing Synaptic plasticity and newly activated synapses. In fact, proteasome activity was required for the consolidation of an otherwise transient potentiation (early-LTP) into late-LTP by strong tetanization of a separate afferent pathway both in the "weak-before-strong" and in the "strong-before-weak" two-pathway paradigms [Frey and Morris (1997) Nature 385:533-536; Frey and Morris (1998) Neuropharmacology 37:545-552], suggesting that proteasome activity plays a role in the Synaptic Tagging and capture of plasticity-related proteins at stimulated synapses. Additionally, proteasome inhibition abrogated immunity against heteroSynaptic depotentiation of an established late-LTP when applied during weak tetanic stimulation in the "strong-before-weak" two-pathway paradigm. Such a heteroSynaptic destabilizing effect of proteasome inhibition was abolished by concomitant inhibition of N-methyl-d-aspartate (NMDA) receptors, suggesting that it is an active process. Together, these results indicate that the proteasome plays important roles in the establishment of late-LTP and in the preservation of potentiated synapses when a subsequent Synaptic plasticity is induced within the same neuronal population.
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Interfering with the Actin Network and Its Effect on Long-Term Potentiation and Synaptic Tagging in Hippocampal CA1 Neurons in Slices In Vitro
Journal of Neuroscience, 2009Co-Authors: Binu Ramachandran, Julietta Uta FreyAbstract:Long-term potentiation (LTP) is a cellular correlate for memory formation, which requires the dynamic changes of the actin cytoskeleton. As shown by others, the polymerization of the actin network is important for early stages of LTP. Here, we investigated the role of actin dynamics in Synaptic Tagging and particularly in the induction of protein synthesis-dependent late-LTP in the CA1 region in hippocampal slices in vitro. We found that the inhibition of actin polymerization affects protein synthesis-independent early-LTP, prevents late-LTP, and interferes with Synaptic Tagging in apical dendrites of hippocampal CA1. The transformation of early-LTP into late-LTP was blocked by the application of the structurally different actin polymerization inhibitors latrunculin A or cytochalasin D. We suggest that the actin network is required for early “housekeeping” processes to induce and maintain early-LTP. Furthermore, inhibition of actin dynamics negatively interacts with the setting of the Synaptic Tagging complex. We propose actin as a further tag-specific molecule in apical CA1 dendrites where it is directly involved in the Tagging/capturing machinery. Consequently, inhibition of the actin network prevents the interaction of Tagging complexes with plasticity-related proteins. This results in the prevention of late-LTP by inhibition of the actin network during LTP induction.
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chapter 7 Synaptic Tagging and cross Tagging and related associative reinforcement processes of functional plasticity as the cellular basis for memory formation
Progress in Brain Research, 2008Co-Authors: Sabine Martina Frey, Julietta Uta FreyAbstract:Abstract We focus on new properties of cellular and network processes of memory formation involving ‘Synaptic Tagging’ and ‘cross-Tagging’ during long-term potentiation (LTP) and long-term depression (LTD) as well as associative heteroSynaptic interactions, the latter of which are characterized by a time-window of about 1 h. About 20 years ago we showed for the first time that the maintenance of LTP, like memory storage, depends on intact protein synthesis and thus consists of at least two temporal phases. Later, similar properties for LTD were shown by our own and other laboratories. Here we describe the requirements for the induction of the transient early-LTP/LTD and of the protein synthesis-dependent late-LTP/LTD. Late-LTP/LTD depend on the associative activation of heteroSynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory reinforcing inputs within specific, effective time-windows during their induction. The induction of late-LTP/LTD is characterized by novel, late-associative properties such as ‘Synaptic Tagging’, ‘cross-Tagging’ and ‘late-associative reinforcement’. All of these phenomena require the associative setting of Synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. ‘Synaptic Tagging’ guarantees input specificity, ‘cross-Tagging’ determines the interaction between LTP and LTD in a neuron, and thus both are required for the specific processing of afferent signals for the establishment of late-LTP/LTD. ‘Late-associative reinforcement’ describes a process where early-LTP/LTD by the co-activation of modulatory inputs can be transformed into late-LTP/LTD in activated synapses where a tag is set. Recent experiments in the freely moving rat revealed a number of modulatory brain structures involved in the transformation of early-plasticity events into long-lasting ones. Further to this, we have characterized time-windows and activation patterns to be effective in the reinforcement process. Studies using a combined electrophysiological and behavioural approach revealed the physiological relevance of these reinforcement processes, which is also supported by fMRI studies in humans, which led to the hypothesis outlined here on cellular and system memory-formation by late-associative heteroSynaptic interactions at the cellular level during functional plasticity events.
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Chapter 7 ‘Synaptic Tagging’ and ‘cross-Tagging’ and related associative reinforcement processes of functional plasticity as the cellular basis for memory formation
Progress in Brain Research, 2008Co-Authors: Sabine Martina Frey, Julietta Uta FreyAbstract:Abstract We focus on new properties of cellular and network processes of memory formation involving ‘Synaptic Tagging’ and ‘cross-Tagging’ during long-term potentiation (LTP) and long-term depression (LTD) as well as associative heteroSynaptic interactions, the latter of which are characterized by a time-window of about 1 h. About 20 years ago we showed for the first time that the maintenance of LTP, like memory storage, depends on intact protein synthesis and thus consists of at least two temporal phases. Later, similar properties for LTD were shown by our own and other laboratories. Here we describe the requirements for the induction of the transient early-LTP/LTD and of the protein synthesis-dependent late-LTP/LTD. Late-LTP/LTD depend on the associative activation of heteroSynaptic inputs, i.e. the synergistic activation of glutamatergic and modulatory reinforcing inputs within specific, effective time-windows during their induction. The induction of late-LTP/LTD is characterized by novel, late-associative properties such as ‘Synaptic Tagging’, ‘cross-Tagging’ and ‘late-associative reinforcement’. All of these phenomena require the associative setting of Synaptic tags as well as the availability of plasticity-related proteins (PRPs) and they are restricted to functional dendritic compartments, in general. ‘Synaptic Tagging’ guarantees input specificity, ‘cross-Tagging’ determines the interaction between LTP and LTD in a neuron, and thus both are required for the specific processing of afferent signals for the establishment of late-LTP/LTD. ‘Late-associative reinforcement’ describes a process where early-LTP/LTD by the co-activation of modulatory inputs can be transformed into late-LTP/LTD in activated synapses where a tag is set. Recent experiments in the freely moving rat revealed a number of modulatory brain structures involved in the transformation of early-plasticity events into long-lasting ones. Further to this, we have characterized time-windows and activation patterns to be effective in the reinforcement process. Studies using a combined electrophysiological and behavioural approach revealed the physiological relevance of these reinforcement processes, which is also supported by fMRI studies in humans, which led to the hypothesis outlined here on cellular and system memory-formation by late-associative heteroSynaptic interactions at the cellular level during functional plasticity events.
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Identification of Compartment- and Process-Specific Molecules Required for “Synaptic Tagging” during Long-Term Potentiation and Long-Term Depression in Hippocampal CA1
Journal of Neuroscience, 2007Co-Authors: Sreedharan Sajikumar, Sheeja Navakkode, Julietta Uta FreyAbstract:Protein synthesis-dependent forms of hippocampal long-term potentiation (late LTP) and long-term depression (late LTD) are prominent cellular mechanisms underlying memory formation. Recent data support the hypothesis that neurons store relevant information in dendritic functional compartments during late LTP and late LTD rather than in single synapses. It has been suggested that processes of “Synaptic Tagging” are restricted to such functional compartments. Here, we show that in addition to apical CA1 dendrites, Synaptic Tagging also takes place within basal CA1 dendritic compartments after LTP induction. We present data that Tagging in the basal dendrites is restricted to these compartments. Plasticity-related proteins, partially nonspecific to the locally induced process, are synthesized in dendritic compartments and then captured by local, process-specific Synaptic tags. We support these findings in two ways: (1) late LTP/LTD, locally induced in apical or basal (late LTP) dendrites of hippocampal CA1 neurons, does not spread to the basal or apical compartment, respectively; (2) the specificity of the Synaptic plasticity event is achieved by the activation of process- and compartment-specific Synaptic tag molecules. We have identified calcium/calmodulin-dependent protein kinase II as the first LTP-specific and extracellular signal-regulated kinase 1/2 as LTD-specific tag molecules in apical dendritic CA1 compartments, whereas either protein kinase A or protein kinase Mζ mediates LTP-specific tags in basal dendrites.
Haruhiko Bito - One of the best experts on this subject based on the ideXlab platform.
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Inverse Synaptic Tagging: An inactive synapse-specific mechanism to capture activity-induced Arc/arg3.1 and to locally regulate spatial distribution of Synaptic weights.
Seminars in Cell & Developmental Biology, 2018Co-Authors: Hiroyuki Okuno, Keiichiro Minatohara, Haruhiko BitoAbstract:Long-lasting forms of Synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are fundamental cellular mechanisms underlying learning and memory. The Synaptic Tagging and capture (STC) hypothesis has provided a theoretical framework on how products of activity-dependent genes may interact with potentiated synapses to facilitate and maintain such long-lasting Synaptic plasticity. Although Arc/arg3.1 was initially assumed to participate in STC processes during LTP, accumulating evidence indicated that Arc/arg3.1 might rather contribute in weakening of Synaptic weights than in their strengthening. In particular, analyses of Arc/Arg3.1 protein dynamics and function in the dendrites after plasticity-inducing stimuli have revealed a new type of inactivity-dependent redistribution of Synaptic weights, termed "inverse Synaptic Tagging". The original Synaptic Tagging and inverse Synaptic Tagging likely co-exist and are mutually non-exclusive mechanisms, which together may help orchestrate the redistribution of Synaptic weights and promote the enhancement and maintenance of their contrast between potentiated and non-potentiated synapses during the late phase of long-term Synaptic plasticity. In this review, we describe the inverse Synaptic Tagging mechanism that controls Synaptic dynamics of Arc/Arg3.1, an immediate early gene product which is captured and preferentially targeted to non-potentiated synapses, and discuss its impact on neuronal circuit refinement and cognitive function.
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inverse Synaptic Tagging an inactive synapse specific mechanism to capture activity induced arc arg3 1 and to locally regulate spatial distribution of Synaptic weights
Seminars in Cell & Developmental Biology, 2017Co-Authors: Hiroyuki Okuno, Keiichiro Minatohara, Haruhiko BitoAbstract:Long-lasting forms of Synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are fundamental cellular mechanisms underlying learning and memory. The Synaptic Tagging and capture (STC) hypothesis has provided a theoretical framework on how products of activity-dependent genes may interact with potentiated synapses to facilitate and maintain such long-lasting Synaptic plasticity. Although Arc/arg3.1 was initially assumed to participate in STC processes during LTP, accumulating evidence indicated that Arc/arg3.1 might rather contribute in weakening of Synaptic weights than in their strengthening. In particular, analyses of Arc/Arg3.1 protein dynamics and function in the dendrites after plasticity-inducing stimuli have revealed a new type of inactivity-dependent redistribution of Synaptic weights, termed "inverse Synaptic Tagging". The original Synaptic Tagging and inverse Synaptic Tagging likely co-exist and are mutually non-exclusive mechanisms, which together may help orchestrate the redistribution of Synaptic weights and promote the enhancement and maintenance of their contrast between potentiated and non-potentiated synapses during the late phase of long-term Synaptic plasticity. In this review, we describe the inverse Synaptic Tagging mechanism that controls Synaptic dynamics of Arc/Arg3.1, an immediate early gene product which is captured and preferentially targeted to non-potentiated synapses, and discuss its impact on neuronal circuit refinement and cognitive function.
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Deciphering the molecular rules governing Synaptic targeting of the memory-related protein Arc.
Communicative & Integrative Biology, 2012Co-Authors: Ryang Kim, Hiroyuki Okuno, Haruhiko BitoAbstract:Neurons express new gene transcripts and proteins upon receiving Synaptic inputs, and these events are essential for achieving proper neuronal wiring, adequate Synaptic plasticity, and updatable memory. However, the biological impact of new gene expression on input-specific Synaptic potentiation remains largely elusive, in part because the cell biological and biochemical mechanisms for Synaptic targeting of newly synthesized proteins has remained obscure. A new study investigating the targeting of the memory related protein Arc from the soma to the synapses teases apart a novel “inverse” Synaptic Tagging mechanism that enables Arc to specifically target the un-potentiated synapses, thereby helping to maintain the contrast of Synaptic weight between strengthened and weak synapses.
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Synaptic Tagging and capture differential role of distinct calcium calmodulin kinases in protein synthesis dependent long term potentiation
The Journal of Neuroscience, 2010Co-Authors: Roger L. Redondo, Hiroyuki Okuno, Haruhiko Bito, Patrick A. Spooner, Bruno G. Frenguelli, Richard G. M. MorrisAbstract:Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting ~3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The Synaptic Tagging and capture hypothesis explains this heteroSynaptic influence on persistence in terms of a distinction between local mechanisms of Synaptic Tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for >10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which Synaptic potentiation, and possibly memories, become stabilized.
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Synaptic Tagging and Capture: Differential Role of Distinct Calcium/Calmodulin Kinases in Protein Synthesis-Dependent Long-Term Potentiation
Journal of Neuroscience, 2010Co-Authors: Roger L. Redondo, Hiroyuki Okuno, Haruhiko Bito, Patrick A. Spooner, Bruno G. Frenguelli, Richard G. M. MorrisAbstract:Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting ~3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The Synaptic Tagging and capture hypothesis explains this heteroSynaptic influence on persistence in terms of a distinction between local mechanisms of Synaptic Tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for >10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which Synaptic potentiation, and possibly memories, become stabilized.
Ted Abel - One of the best experts on this subject based on the ideXlab platform.
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Sleep deprivation impairs Synaptic Tagging in mouse hippocampal slices.
Neurobiology of Learning and Memory, 2018Co-Authors: Christopher G. Vecsey, Ted Huang, Ted AbelAbstract:Abstract Metaplasticity refers to the ability of experience to alter Synaptic plasticity, or modulate the strength of neuronal connections. Sleep deprivation has been shown to have a negative impact on Synaptic plasticity, but it is unknown whether sleep deprivation also influences processes of metaplasticity. Therefore, we tested whether 5 h of total sleep deprivation (SD) in mice would impair hippocampal Synaptic Tagging and capture (STC), a form of heteroSynaptic metaplasticity in which combining strong stimulation in one Synaptic input with weak stimulation at another input allows the weak input to induce long-lasting Synaptic strengthening. STC in stratum radiatum of area CA1 occurred normally in control mice, but was impaired following SD. After SD, potentiation at the weakly stimulated synapses decayed back to baseline within 2 h. Thus, sleep deprivation disrupts a prominent form of metaplasticity in which two independent inputs interact to generate long-lasting LTP.
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PKA Anchoring and Synaptic Tagging and Capture
Synaptic Tagging and Capture, 2014Co-Authors: Alan J. Park, Ted AbelAbstract:Synaptic Tagging and capture (STC) hypothesis has been receiving increasing attention because it reflects heteroSynaptic association of information processing during memory formation in the brain. Indeed, electrophysiological and behavioral studies suggest that STC is a better cellular model for memory formation than the conventional homoSynaptic experiment. In STC, a short-lasting potentiation in one pathway becomes persistent when it is paired with a long-lasting potentiation in the other independent pathway. It has been proposed that the setting of synapse-specific tag and capture of non-synapse-specific diffusible gene products by the tag determines the fate of each pathway. However, the mechanism of STC is still elusive and three major questions should be answered: (1) What is the tag and how does it modulate synapse-specific plasticity? (2) How does the tag capture gene products? (3) What are the gene products and how are they produced? Although several molecules and processes have been suggested to answer to these questions, they only provide partial explanations about the phenomenon. Here, this article will discuss how PKA modulates synapse-specific neuronal processing by coordinating signaling molecules and processes through PKA anchoring proteins, and how anchored PKA is involved in the generation and capture of plasticity-related gene products. Having PKA as a key molecule, the goal of this article is to provide a unified model of STC that addresses the key questions.
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A preSynaptic role for PKA in Synaptic Tagging and memory
Neurobiology of Learning and Memory, 2014Co-Authors: Alan J. Park, Ted Huang, Robbert Havekes, Jennifer H. K. Choi, Vincent Luczak, Ting Nie, Ted AbelAbstract:Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postSynaptic mechanisms, preSynaptically anchored PKA may contribute to Synaptic plasticity and memory because PKA also regulates preSynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of Synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of Synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of Synaptic vesicles is supported by biochemical assays showing that Synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for preSynaptically anchored PKA in pathway-specific Synaptic Tagging and long-term contextual fear memory. These results suggest that a preSynaptically compartmentalized PKA is critical for Synaptic plasticity and memory by regulating the readily releasable pool of Synaptic vesicles.
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Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in Synaptic Tagging
European Journal of Neuroscience, 2006Co-Authors: Jennie Z. Young, Carolina Isiegas, Ted Abel, Peter V. NguyenAbstract:The late-phase of long-term potentiation (L-LTP) in hippocampal area CA1 requires gene expression and de novo protein synthesis but it is expressed in an input-specific manner. The 'Synaptic tag' theory proposes that gene products can only be captured and utilized at synapses that have been 'tagged' by previous activity. The mechanisms underlying Synaptic Tagging, and its activity dependence, are largely undefined. Previously, we reported that low-frequency stimulation (LFS) decreases the stability of L-LTP in a cell-wide manner by impairing Synaptic Tagging. We show here that a phosphatase inhibitor, okadaic acid, blocked homoSynaptic and heteroSynaptic inhibition of L-LTP by prior LFS. In addition, prior LFS homoSynaptically and heteroSynaptically impaired chemically induced Synaptic facilitation elicited by forskolin/3-isobutyl-1-methylxanthine, suggesting that there is a cell-wide dampening of cAMP/protein kinase A (PKA) signaling concurrent with phosphatase activation. We propose that prior LFS impairs expression of L-LTP by inhibiting Synaptic Tagging through its actions on the cAMP/PKA pathway. In support of this notion, we show that hippocampal slices from transgenic mice that have genetically reduced hippocampal PKA activity display impaired Synaptic capture of L-LTP. An inhibitor of PKA, KT-5720, also blocked Synaptic capture of L-LTP. Moreover, pharmacological activation of the cAMP/PKA pathway can produce a Synaptic tag to capture L-LTP expression, resulting in persistent Synaptic facilitation. Collectively, our results show that PKA is critical for Synaptic Tagging and for input-specific L-LTP. PKA-mediated signaling can be constrained by prior episodes of Synaptic activity to regulate subsequent L-LTP expression and perhaps control the integration of multiple Synaptic events over time.
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Compartmentalized PKA signaling events are required for Synaptic Tagging and capture during hippocampal late-phase long-term potentiation
European Journal of Cell Biology, 2006Co-Authors: Ted Huang, Conor B. Mcdonough, Ted AbelAbstract:Synaptic plasticity, the activity-dependent change in the strength of neuronal connections, is a proposed cellular mechanism of memory storage that is critically regulated by protein kinases such as cAMP-dependent protein kinase (PKA). Despite the fact that a neuron contains thousands of synapses, the expression of Synaptic plasticity can be specific to subsets of synapses. This is surprising because signal transduction pathways underlying Synaptic plasticity involve diffusible second messenger molecules such as cAMP and diffusible proteins such as the catalytic subunit of PKA. One way in which this specificity can be achieved is by the localization of signal transduction molecules to specific subcellular domains. Spatial compartmentalization of PKA signaling is achieved via binding to A kinase-anchoring proteins (AKAPs). We report here that pharmacological inhibition of PKA anchoring impairs Synaptically activated late-phase long-term potentiation (L-LTP) in hippocampal slices. In contrast, potentiation that is induced by the pharmacological activation of the cAMP/PKA pathway, which can potentially affect all synapses within the neuron, is not impaired by inhibition of PKA anchoring. These results suggest that PKA anchoring may be particularly important for events that occur at the synapse during the induction of L-LTP, such as Synaptic Tagging and capture. Indeed, our results demonstrate that blocking PKA anchoring impairs Synaptic Tagging and capture. Thus our data highlight the idea that PKA anchoring may allow for specific populations of synapses to change in Synaptic strength in the face of plasticity-related transcription that is cell-wide.
