Journal articles on the topic 'Ltp protein'
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1
Abbas, Abdul-Karim, Agnès Villers, and Laurence Ris. "Temporal phases of long-term potentiation (LTP): myth or fact?" Reviews in the Neurosciences 26, no. 5 (October 1, 2015): 507–46. http://dx.doi.org/10.1515/revneuro-2014-0072.
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AbstractLong-term potentiation (LTP) remains the most widely accepted model for learning and memory. In accordance with this belief, the temporal differentiation of LTP into early and late phases is accepted as reflecting the differentiation of short-term and long-term memory. Moreover, during the past 30 years, protein synthesis inhibitors have been used to separate the early, protein synthesis-independent (E-LTP) phase and the late, protein synthesis-dependent (L-LTP) phase. However, the role of these proteins has not been formally identified. Additionally, several reports failed to show an effect of protein synthesis inhibitors on LTP. In this review, a detailed analysis of extensive behavioral and electrophysiological data reveals that the presumed correspondence of LTP temporal phases to memory phases is neither experimentally nor theoretically consistent. Moreover, an overview of the time courses of E-LTP in hippocampal slices reveals a wide variability ranging from <1 h to more than 5 h. The existence of all these conflictual findings should lead to a new vision of LTP. We believe that the E-LTP vs. L-LTP distinction, established with protein synthesis inhibitor studies, reflects a false dichotomy. We suggest that the duration of LTP and its dependency on protein synthesis are related to the availability of a set of proteins at synapses and not to the de novo synthesis of plasticity-related proteins. This availability is determined by protein turnover kinetics, which is regulated by previous and ongoing electrical activities and by energy store availability.
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Nynca, Joanna, Mariola A. Dietrich, Barbara Bilińska, Małgorzata Kotula-Balak, Tomasz Kiełbasa, Halina Karol, and Andrzej Ciereszko. "Isolation of lipocalin-type protein from rainbow trout seminal plasma and its localisation in the reproductive system." Reproduction, Fertility and Development 23, no. 2 (2011): 381. http://dx.doi.org/10.1071/rd10118.
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The lipocalin protein family is a large and diverse group of small extracellular proteins characterised by their ability to bind hydrophobic molecules. In the present study, we describe the isolation procedure for rainbow trout seminal plasma protein, characterised by a moderate migration rate during polyacrylamide gel electrophoresis, providing information regarding its basic features and immunohistochemical localisation. This protein was identified as a lipocalin-type protein (LTP). The molecular mass of LTP was found to be 18 848 Da and it was found to lack any carbohydrate components. Only a few Salmoniformes contain LTP in their seminal plasma. The abundance of LTP in the Sertoli and Leydig cells of the testes of the rainbow trout, as well as in secretory cells of the efferent duct, suggests that this protein is specific for rainbow trout milt, where it acts as a lipophilic carrier protein. Moreover, the specific localisation of LTP in the flagella of the spermatozoa suggests a role for LTP in sperm motility. Further experiments are necessary to identify the endogenous ligands for LTP in rainbow trout seminal plasma and to characterise the binding properties of this protein.
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Huang, Y. Y., and E. R. Kandel. "Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization." Learning & Memory 1, no. 1 (1994): 74–82. http://dx.doi.org/10.1101/lm.1.1.74.
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To study how the late phase of long-term potentiation (LTP) in hippocampus arises, we examined the resulting LTP for its time course and its dependence on protein synthesis and different second-messenger kinases by applying various conditioning tetani. We find that one high-frequency train (100 Hz) produces a form of LTP that lasts longer than 1 hr but less than 3 hr (the early phase of LTP, or E-LTP). It is blocked by inhibitors of calcium/calmodulin kinase II (Cam kinase II) but is not affected by an inhibitor of cAMP-dependent protein kinase [protein kinase A (PKA) and the protein synthesis inhibitor anisomycin] nor is it occluded by the cAMP activator forskolin. In contrast, when three high-frequency trains are used, the resulting potentiation persists for at least 6-10 hr. The L-LTP induced by three trains differs from the E-LTP in that it requires new protein synthesis, is blocked by an inhibitor of cAMP-dependent protein kinase, and is occluded by forskolin. These results indicate that the two mechanistically distinctive forms of LTP, a transient, early component (E-LTP) and a more enduring form (L-LTP), can be recruited selectively by changing the number of conditioning tetanic trains. Repeated tetani induce a PKA and protein synthesis-dependent late component that adds to the amplitude and duration of the potentiation induced by a single tetanus.
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Soderling, Thomas R., and Victor A. Derkach. "Postsynaptic protein phosphorylation and LTP." Trends in Neurosciences 23, no. 2 (February 2000): 75–80. http://dx.doi.org/10.1016/s0166-2236(99)01490-3.
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Chong, L. D. "STKE: Protein Translation and LTP." Science 295, no. 5555 (January 25, 2002): 589c—589. http://dx.doi.org/10.1126/science.295.5555.589c.
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Yang, Hong-Wei, Xiao-Dong Hu, Hong-Mei Zhang, Wen-Jun Xin, Ming-Tao Li, Tong Zhang, Li-Jun Zhou, and Xian-Guo Liu. "Roles of CaMKII, PKA, and PKC in the Induction and Maintenance of LTP of C-Fiber-Evoked Field Potentials in Rat Spinal Dorsal Horn." Journal of Neurophysiology 91, no. 3 (March 2004): 1122–33. http://dx.doi.org/10.1152/jn.00735.2003.
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Long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn may be relevant to hyperalgesia, an increased response to noxious stimulation. The mechanism underlying this form of synaptic plasticity is, however, still unclear. Considerable evidence has shown that calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and protein kinase C (PKC) are important for LTP in hippocampus. In this study, the roles of these three protein kinases in the induction and maintenance of LTP of C-fiber-evoked field potentials were evaluated by application of specific inhibitors of CaMKII (KN-93 and AIP), PKA (Rp-CPT-cAMPS), and PKC (chelerythrine and Gö 6983) at the recording segments before and after LTP induction in urethane-anesthetized Sprague-Dawley rats. We found both KN-93 and AIP, when applied at 30 min prior to tetanic stimulation, completely blocked LTP induction. At 30 min after LTP induction, KN-93 and AIP reversed LTP completely, and at 60 min after LTP induction, they depressed spinal LTP in most rats tested. Three hours after LTP induction, however, KN-93 or AIP did not affect the spinal LTP. Rp-CPT-cAMPS, chelerythrine, and Gö 6983 blocked the spinal LTP when applied at 30 min before tetanic stimulation and reversed LTP completely at 15 min after LTP induction. In contrast, at 30 min after LTP induction, the drugs never affected the spinal LTP. These results suggest that activation of CaMKII, PKA, and PKC may be crucial for the induction and the early-phase but not for the late-phase maintenance of the spinal LTP.
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Rizzi, Angela, Raffaella Chini, Riccardo Inchingolo, Valentina Carusi, Franco Pandolfi, Antonio Gasbarrini, and Eleonora Nucera. "Nickel allergy in lipid transfer protein sensitized patients: Prevalence and clinical features." International Journal of Immunopathology and Pharmacology 34 (January 2020): 205873842097489. http://dx.doi.org/10.1177/2058738420974895.
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Nickel (Ni), the main responsible for allergic contact dermatitis worldwide, is also involved in systemic condition called “Systemic Nickel Sulfate Allergy Syndrome (SNAS).” Likewise, IgE-mediated reactivity to Lipid Transfer Protein (LTP) represents the main cause of primary food allergy in adults of Mediterranean countries. We evaluated the prevalence of SNAS in LTP allergic patients and investigated patients’ clinical features with double sensitization (LTP and Ni). A retrospective, single-center, observational study was conducted performing a complete allergological work-up including: (1) skin prick tests; (2) serum specific IgE for plant food allergens and rPru p3 (LTP); (3) patch test with 5% Ni sulfate in petrolatum. We enrolled 140 LTP allergic patients of which 36 patients (25.7% of sample) showed additional positivity to Ni patch test. Patients with double sensitization were more frequently females and reported fewer cutaneous symptoms. Higher values of sIgE for peach, apple, peanut, walnut, grain, corn, and garlic were found in LTP allergic patients, while higher values for hazelnut in the other subgroup. The prevalence of SNAS in the LTP allergic population is clinically relevant. Moreover, the clinical and immunological profiles of patients with double sensitization were different from patients monosensitized to LTP.
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Sheng, Nengyin, Michael A. Bemben, Javier Díaz-Alonso, Wucheng Tao, Yun Stone Shi, and Roger A. Nicoll. "LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes." Proceedings of the National Academy of Sciences 115, no. 15 (March 26, 2018): 3948–53. http://dx.doi.org/10.1073/pnas.1800719115.
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Long-term potentiation (LTP) is a persistent strengthening of synaptic transmission in the brain and is arguably the most compelling cellular and molecular model for learning and memory. Previous work found that both AMPA receptors and exogenously expressed kainate receptors are equally capable of expressing LTP, despite their limited homology and their association with distinct auxiliary subunits, indicating that LTP is far more promiscuous than previously thought. What might these two subtypes of glutamate receptor have in common? Using a single-cell molecular replacement strategy, we demonstrate that the AMPA receptor auxiliary subunit TARP γ-8, via its PDZ-binding motif, is indispensable for both basal synaptic transmission and LTP. Remarkably, kainate receptors and their auxiliary subunits Neto proteins share the same requirement of PDZ-binding domains for synaptic trafficking and LTP. Together, these results suggest that a minimal postsynaptic requirement for LTP is the PDZ binding of glutamate receptors/auxiliary subunits to PSD scaffolding proteins.
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Abbas, Abdul-Karim, Mikhail Dozmorov, Rui Li, Fen-Sheng Huang, Fredrik Hellberg, Jonas Danielson, Ye Tian, Jörgen Ekström, Mats Sandberg, and Holger Wigström. "Persistent LTP without triggered protein synthesis." Neuroscience Research 63, no. 1 (January 2009): 59–65. http://dx.doi.org/10.1016/j.neures.2008.10.008.
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Goto, Jun-Ichi, Satoshi Fujii, Hiroki Fujiwara, Katsuhiko Mikoshiba, and Yoshihiko Yamazaki. "Synaptic plasticity in hippocampal CA1 neurons of mice lacking inositol-1,4,5-trisphosphate receptor-binding protein released with IP3 (IRBIT)." Learning & Memory 29, no. 4 (March 29, 2022): 110–19. http://dx.doi.org/10.1101/lm.053542.121.
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In hippocampal CA1 neurons of wild-type mice, a short tetanus (15 or 20 pulses at 100 Hz) or a standard tetanus (100 pulses at 100 Hz) to a naive input pathway induces long-term potentiation (LTP) of the responses. Low-frequency stimulation (LFS; 1000 pulses at 1 Hz) 60 min after the standard tetanus reverses LTP (depotentiation [DP]), while LFS applied 60 min prior to the standard tetanus suppresses LTP induction (LTP suppression). We investigated LTP, DP, and LTP suppression of both field excitatory postsynaptic potentials and population spikes in CA1 neurons of mice lacking the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-binding protein released with IP3 (IRBIT). The mean magnitudes of LTP induced by short and standard tetanus were not different in mutant and wild-type mice. In contrast, DP and LTP suppression were attenuated in mutant mice, whereby the mean magnitude of responses after LFS or tetanus were significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, IRBIT is involved in DP and LTP suppression, but is not essential for LTP. The attenuation of DP and LTP suppression in mice lacking IRBIT indicates that this protein, released during or after priming stimulations, determines the direction of LTP expression after the delivery of subsequent stimulations.
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Stevens-Bullmore, Hamish, Don Kulasiri, and Sandhya Samarasinghe. "A Modeling and Analysis Study Reveals That CaMKII in Synaptic Plasticity Is a Dominant Affecter in CaM Systems in a T286 Phosphorylation-Dependent Manner." Molecules 27, no. 18 (September 14, 2022): 5974. http://dx.doi.org/10.3390/molecules27185974.
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NMDAR-dependent synaptic plasticity in the hippocampus consists of two opposing forces: long-term potentiation (LTP), which strengthens synapses and long-term depression (LTD), which weakens synapses. LTP and LTD are associated with memory formation and loss, respectively. Synaptic plasticity is controlled at a molecular level by Ca2+-mediated protein signaling. Here, Ca2+ binds the protein, calmodulin (CaM), which modulates synaptic plasticity in both directions. This is because Ca2+-bound CaM activates both LTD-and LTP-inducing proteins. Understanding how CaM responds to Ca2+ signaling and how this translates into synaptic plasticity is therefore important to understanding synaptic plasticity induction. In this paper, CaM activation by Ca2+ and calmodulin binding to downstream proteins was mathematically modeled using differential equations. Simulations were monitored with and without theoretical knockouts and, global sensitivity analyses were performed to determine how Ca2+/CaM signaling occurred at various Ca2+ signals when CaM levels were limiting. At elevated stimulations, the total CaM pool rapidly bound to its protein binding targets which regulate both LTP and LTD. This was followed by CaM becoming redistributed from low-affinity to high-affinity binding targets. Specifically, CaM was redistributed away from LTD-inducing proteins to bind the high-affinity LTP-inducing protein, calmodulin-dependent kinase II (CaMKII). In this way, CaMKII acted as a dominant affecter and repressed activation of opposing CaM-binding protein targets. The model thereby showed a novel form of CaM signaling by which the two opposing pathways crosstalk indirectly. The model also found that CaMKII can repress cAMP production by repressing CaM-regulated proteins, which catalyze cAMP production. The model also found that at low Ca2+ stimulation levels, typical of LTD induction, CaM signaling was unstable and is therefore unlikely to alone be enough to induce synaptic depression. Overall, this paper demonstrates how limiting levels of CaM may be a fundamental aspect of Ca2+ regulated signaling which allows crosstalk among proteins without requiring directly interaction.
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Xue, Lei, Fan Zhang, Xianhua Chen, Junji Lin, and Jian Shi. "PDZ protein mediated activity-dependent LTP/LTD developmental switch at rat retinocollicular synapses." American Journal of Physiology-Cell Physiology 298, no. 6 (June 2010): C1572—C1582. http://dx.doi.org/10.1152/ajpcell.00012.2010.
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The insertion of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors into the plasma membrane and removal via internalization are essential for regulating synaptic strength, which underlies the basic mechanism of learning and memory. The retinocollicular pathway undergoes synaptic refinement during development and shows a wide variety of long-term synaptic changes; however, still little is known about its underlying molecular regulation. Here we report a rapid developmental long-term potentiation (LTP)/long-term depression (LTD) switch and its intracellular mechanism at the rat retinocollicular pathway from postnatal day 5 (P5) to P14. Before P9, neurons always exhibited LTP, whereas LTD was observed only after P10. Blockade of GluR2/3-glutamate receptor-interacting protein (GRIP)/AMPA-receptor-binding protein (ABP)/protein interacting with C kinase 1 (PICK1) interactions with pep2-SVKI could sustain the LTP after P10. This suggests that the LTP/LTD switch relied on PDZ protein activities. Selective interruption of GluR2/3-PICK1 binding by pep2-EVKI blocked the long-lasting effects of both LTP and LTD, suggesting a role for PICK1 in the maintenance of long-term synaptic plasticity. Interestingly, synaptic expression of GRIP increased more than twofold from P7 to P11, whereas ABP and PICK1 expression levels remained stable. Blockade of spontaneous retinal input suppressed this increase and abolished the LTP/LTD switch. These results suggest that the increased GRIP synaptic expression may be a key regulatory factor in mediating the activity-dependent developmental LTP/LTD switch, whereas PICK1 may be required for both LTP and LTD to maintain their long-term effects.
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Yang, Hong-Wei, Li-Jun Zhou, Neng-Wei Hu, Wen-Jun Xin, and Xian-Guo Liu. "Activation of Spinal D1/D5 Receptors Induces Late-Phase LTP of C-Fiber–Evoked Field Potentials in Rat Spinal Dorsal Horn." Journal of Neurophysiology 94, no. 2 (August 2005): 961–67. http://dx.doi.org/10.1152/jn.01324.2004.
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Long-term potentiation (LTP) of C-fiber–evoked field potentials in spinal dorsal horn may be relevant to pathological pain. Our previous work has shown that the late phase of the spinal LTP is protein synthesis–dependent. Considerable evidence has accumulated that dopamine D1/D5 receptors are important for late-phase LTP in hippocampus. In this study, the role of D1/D5 receptors in LTP of C-fiber–evoked field potentials in spinal dorsal horn was evaluated in urethan-anesthetized Sprague-Dawley rats. We found the following. 1) Spinal application of SKF 38393, a D1/D5 receptor agonist, induced a slowly developed LTP of C-fiber–evoked field potentials, lasting for >10 h, and the effect was blocked by the D1/D5 antagonist SCH 23390, whereas a D2 receptor agonist (quinpirole) induced depression of C-fiber responses, lasting for 2 h. 2) The potentiation produced by D1/D5 receptor agonist occluded the late phase but not the early phase of the spinal LTP produced by tetanic stimulation. 3) SCH 23390 selectively depressed the late-phase LTP, when applied 40 min before tetanic stimulation. 4) The D1/D5 agonist-induced potentiation is blocked by the protein synthesis inhibitor anisomycin. 5) Activation of protein kinase A by spinal application of 8-Br-cAMP also induced spinal LTP, and the action occluded the potentiation induced by the D1/D5 receptor agonist. These results suggest that the spinal D1/D5 receptors participate in the protein synthesis–dependent late-phase LTP of C-fiber–evoked field potentials in spinal dorsal horn through the cAMP signaling pathway.
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Hu, Neng-Wei, Hong-Mei Zhang, Xiao-Dong Hu, Ming-Tao Li, Tong Zhang, Li-Jun Zhou, and Xian-Guo Liu. "Protein Synthesis Inhibition Blocks the Late-Phase LTP of C-Fiber Evoked Field Potentials in Rat Spinal Dorsal Horn." Journal of Neurophysiology 89, no. 5 (May 1, 2003): 2354–59. http://dx.doi.org/10.1152/jn.01027.2002.
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Previous studies have demonstrated that in the hippocampus the maintenance of long-term potentiation (LTP) requires de novo protein synthesis. To investigate the role of protein synthesis in the maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn, which may be relevant to hyperalgesia, protein synthesis inhibitor (either cycloheximide or anisomycin) was applied locally to the recording segments of spinal cord in anesthetized rats, 30 min prior to tetanic stimulation to the sciatic nerve. We found that both cycloheximide and anisomycin selectively inhibited late-phase maintenance of the spinal LTP but affected neither LTP induction nor baseline responses of C-fiber evoked field potentials. In the presence of cycloheximide, LTP of C-fiber evoked field potentials was 281.5 ± 16.5% ( n = 6) of baseline 1 h after tetanic stimulation and the potentiation significantly decreased to 235.5 ± 18.5% at 145 min after tetanic stimulation ( P< 0.05). Afterward, LTP of C-fiber evoked field potentials decreased continuously and at 270 min after tetanic stimulation reached 130.8 ± 18.0%, which was no longer different from baseline ( P > 0.05). Spinal application of anisomycin at 30 min before tetanic stimulation yielded similar results ( n = 6). These results suggest that protein synthesis may be crucial for the late-phase maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn.
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Woo, Newton H., Steven N. Duffy, Ted Abel, and Peter V. Nguyen. "Genetic and Pharmacological Demonstration of Differential Recruitment of cAMP-Dependent Protein Kinases by Synaptic Activity." Journal of Neurophysiology 84, no. 6 (December 1, 2000): 2739–45. http://dx.doi.org/10.1152/jn.2000.84.6.2739.
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cAMP-dependent protein kinase (PKA) is believed to play a critical role in the expression of long-lasting forms of hippocampal long-term potentiation (LTP). Can distinct patterns of synaptic activity induce forms of LTP that require different isoforms of PKA? To address this question, we used transgenic mice that have genetically reduced hippocampal PKA activity, and a specific pharmacological inhibitor of PKA, Rp-cAMPS. Transgenic mice [R(AB) mice] that express an inhibitory form of a particular type of regulatory subunit of PKA (type-Iα) showed significantly reduced LTP in area CA1 of hippocampal slices as compared with slices from wild-type mice. This impairment of LTP expression was evident when LTP was induced by applying repeated, temporally spaced stimulation (4 1-s bursts of 100-Hz applied once every 5 min). In contrast, LTP induced by applying just 60 pulses in a theta-burst pattern was normal in slices from R(AB) mice as compared with slices from wild-type mice. We found that Rp-cAMPS blocked the expression of LTP induced by both spaced tetra-burst and compressed theta-burst stimulation in hippocampal slices of wild-type and R(AB) mice, respectively. Since Rp-cAMPS is a PKA inhibitor that is not selective for any particular isoform of PKA and these R(AB) mice show reduced hippocampal PKA activity resulting from genetic manipulation of a single isoform of PKA regulatory subunit, our data support the idea that distinct patterns of synaptic activity can produce different forms of LTP that significantly engage different isoforms of PKA. In particular, theta-burst LTP significantly recruits isoforms of PKA containing regulatory subunits other than the mutant RIα subunit, whereas tetra-burst LTP requires PKA isoforms containing the mutant RIα subunit. Thus, altering both the total amount of imposed synaptic activity and the temporal spacing between bursts of imposed activity may subtly modulate the PKA dependence of hippocampal LTP by engaging distinct isoforms of PKA. In a broader context, our findings suggest that synaptic plasticity in the mammalian brain might be importantly regulated by activity-dependent recruitment of different isoforms of key signal transduction molecules.
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Luu, Percy, and Robert C. Malenka. "Spike Timing-Dependent Long-Term Potentiation in Ventral Tegmental Area Dopamine Cells Requires PKC." Journal of Neurophysiology 100, no. 1 (July 2008): 533–38. http://dx.doi.org/10.1152/jn.01384.2007.
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Long-term potentiation (LTP) of excitatory synapses on ventral tegmental area (VTA) dopamine (DA) cells is thought to play an important role in mediating some of the behavioral effects of drugs of abuse yet little is known about its underlying mechanisms. We find that spike timing-dependent LTP (STD LTP) in VTA DA cells is absent in slices prepared from mice previously administered cocaine, suggesting that cocaine-induced LTP and STD LTP share underlying mechanisms. This form of STD LTP is dependent on NMDA receptor (NMDAR) activation and a rise in postsynaptic calcium but surprisingly was not affected by an inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII). It was blocked by antagonists of conventional isoforms of PKC, whereas activation of protein kinase C (PKC) using a phorbol ester enhanced synaptic strength. These results suggest that NMDAR-mediated activation of PKC, but not CaMKII, is a critical trigger for LTP in VTA DA cells.
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Auerbach, Benjamin D., and Mark F. Bear. "Loss of the Fragile X Mental Retardation Protein Decouples Metabotropic Glutamate Receptor Dependent Priming of Long-Term Potentiation From Protein Synthesis." Journal of Neurophysiology 104, no. 2 (August 2010): 1047–51. http://dx.doi.org/10.1152/jn.00449.2010.
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Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). FMRP is a negative regulator of local mRNA translation downstream of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation. In the absence of FMRP there is excessive mGluR-dependent protein synthesis, resulting in exaggerated mGluR-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus. Understanding disease pathophysiology is critical for development of therapies for FXS and the question arises of whether it is more appropriate to target excessive LTD or excessive mGluR-dependent protein synthesis. Priming of long-term potentiation (LTP) is a qualitatively different functional consequence of Gp1 mGluR-stimulated protein synthesis at the same population of CA1 synapses where LTD can be induced. Therefore we determined if LTP priming, like LTD, is also disrupted in the Fmr1 knockout (KO) mouse. We found that mGluR-dependent priming of LTP is of comparable magnitude in wild-type (WT) and Fmr1 KO mice. However, whereas LTP priming requires acute stimulation of protein synthesis in WT mice, it is no longer protein synthesis dependent in the Fmr1 KO. These experiments show that the dysregulation of mGluR-mediated protein synthesis seen in Fmr1 KO mice has multiple consequences on synaptic plasticity, even within the same population of synapses. Furthermore, it suggests that there is a bifurcation in the Gp1 mGluR signaling pathway, with one arm triggering synaptic modifications such as LTP priming and LTD and the other stimulating protein synthesis that is permissive for these modifications.
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Hoeffer, Charles A., Emanuela Santini, Tao Ma, Elizabeth C. Arnold, Ashley M. Whelan, Helen Wong, Philippe Pierre, Jerry Pelletier, and Eric Klann. "Multiple components of eIF4F are required for protein synthesis-dependent hippocampal long-term potentiation." Journal of Neurophysiology 109, no. 1 (January 1, 2013): 68–76. http://dx.doi.org/10.1152/jn.00342.2012.
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Persistent forms of synaptic plasticity are widely thought to require the synthesis of new proteins. This feature of long-lasting forms of plasticity largely has been demonstrated using inhibitors of general protein synthesis, such as either anisomycin or emetine. However, these drugs, which inhibit elongation, cannot address detailed questions about the regulation of translation initiation, where the majority of translational control occurs. Moreover, general protein synthesis inhibitors cannot distinguish between cap-dependent and cap-independent modes of translation initiation. In the present study, we took advantage of two novel compounds, 4EGI-1 and hippuristanol, each of which targets a different component of the eukaryotic initiation factor (eIF)4F initiation complex, and investigated their effects on long-term potentiation (LTP) at CA3-CA1 synapses in the hippocampus. We found that 4EGI-1 and hippuristanol both attenuated long-lasting late-phase LTP induced by two different stimulation paradigms. We also found that 4EGI-1 and hippuristanol each were capable of blocking the expression of newly synthesized proteins immediately after the induction of late-phase LTP. These new pharmacological tools allow for a more precise dissection of the role played by translational control pathways in synaptic plasticity and demonstrate the importance of multiple aspects of eIF4F in processes underlying hippocampal LTP, laying the foundation for future studies investigating the role of eIF4F in hippocampus-dependent memory processes.
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Cui, Hui Song, So Young Joo, Yoon Soo Cho, Ji Heon Park, June-Bum Kim, and Cheong Hoon Seo. "Effect of Combining Low Temperature Plasma, Negative Pressure Wound Therapy, and Bone Marrow Mesenchymal Stem Cells on an Acute Skin Wound Healing Mouse Model." International Journal of Molecular Sciences 21, no. 10 (May 23, 2020): 3675. http://dx.doi.org/10.3390/ijms21103675.
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Low-temperature plasma (LTP; 3 min/day), negative pressure wound therapy (NPWT; 4 h/day), and bone marrow mesenchymal stem cells (MSCs; 1 × 106 cells/day) were used as mono- and combination therapy in an acute excisional skin wound-healing ICR mouse model. These therapies have been beneficial in treating wounds. We investigated the effectiveness of monotherapy with LTP, NPWT, and MSC and combination therapy with LTP + MSC, LTP + NPWT, NPWT + MSC, and LTP + NPWT + MSC on skin wounds in mice for seven consecutive days. Gene expression, protein expression, and epithelial thickness were analyzed using real time polymerase chain reaction (RT-qPCR), western blotting, and hematoxylin and eosin staining (H&E), respectively. Wound closure was also evaluated. Wound closure was significantly accelerated in monotherapy groups, whereas more accelerated in combination therapy groups. Tumor necrosis factor-α (TNF-α) expression was increased in the LTP monotherapy group but decreased in the NPWT, MSC, and combination therapy groups. Expressions of vascular endothelial growth factor (VEGF), α-smooth muscle actin (α-SMA), and type I collagen were increased in the combination therapy groups. Re-epithelialization was also considerably accelerated in combination therapy groups. Our findings suggest that combination therapy with LPT, NPWT, and MSC exert a synergistic effect on wound healing, representing a promising strategy for the treatment of acute wounds.
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Chen, Huan-Xin, Nikolai Otmakhov, Stefan Strack, Roger J. Colbran, and John E. Lisman. "Is Persistent Activity of Calcium/Calmodulin-Dependent Kinase Required for the Maintenance of LTP?" Journal of Neurophysiology 85, no. 4 (April 1, 2001): 1368–76. http://dx.doi.org/10.1152/jn.2001.85.4.1368.
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Calcium/calmodulin-dependent protein kinase II (CaMKII) is concentrated in the postsynaptic density (PSD) and plays an important role in the induction of long-term potentiation (LTP). Because this kinase is persistently activated after the induction, its activity could also be important for LTP maintenance. Experimental tests of this hypothesis, however, have given conflicting results. In this paper we further explore the role of postsynaptic CaMKII in induction and maintenance of LTP. Postsynaptic application of a CaMKII inhibitor [autocamtide-3 derived peptide inhibitor (AC3-I), 2 mM] blocked LTP induction but had no detectable affect on N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, indicating that the primary function of CaMKII in LTP is downstream from NMDA channel function. We next explored various methodological factors that could account for conflicting results on the effect of CaMKII inhibitors on LTP maintenance. In contrast to our previous work, we now carried out experiments at higher temperature (33°C), used slices from adult animals, and induced LTP using a tetanic stimulation. However, we still found that LTP maintenance was not affected by postsynaptic application of AC3-I. Furthermore the inhibitor did not block LTP maintenance under conditions designed to enhance the Ca2+-dependent activity of protein phosphatases 1 and 2B (elevated Ca2+, calmodulin, and an inhibitor of protein kinase A). We also tested the possibility that CaMKII inhibitor might not be able to affect CaMKII once it was inserted into the PSD. In whole-brain extracts, AC3-I blocked autophosphorylation of both soluble and particulate/PSD CaMKII with similar potencies although the potency of the inhibitor toward other CaMKII substrates varied. Thus we were unable to demonstrate a functional role of persistent Ca2+-independent CaMKII activity in LTP maintenance. Possible explanations of the data are discussed.
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O'Dell, T. J., and E. R. Kandel. "Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases." Learning & Memory 1, no. 2 (1994): 129–39. http://dx.doi.org/10.1101/lm.1.2.129.
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In the CA1 region of adult guinea pig hippocampal slices, long trains of theta frequency (5 Hz) stimulation produced a small enhancement of basal synaptic transmission but depressed the strength of synaptic transmission at synapses that had recently undergone long-term potentiation (LTP). Five hertz stimulation delivered immediately prior to high-frequency stimulation also inhibited the subsequent induction of LTP. The depression of potentiated synapses by 5 Hz stimulation (depotentiation) was blocked by 2-amino-5-phosphonovalerate and was observed only during the early phases of LTP. Furthermore, the protein phosphatase inhibitors okadaic acid and calyculin A blocked both depotentiation and the ability of 5 Hz stimulation to inhibit subsequent LTP, suggesting that protein phosphatases are involved in the ability of 5 Hz stimulation to modulate synaptic plasticity in the CA1 region of the hippocampus.
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Scharf, Matthew T., Newton H. Woo, K. Matthew Lattal, Jennie Z. Young, Peter V. Nguyen, and Ted Abel. "Protein Synthesis Is Required for the Enhancement of Long-Term Potentiation and Long-Term Memory by Spaced Training." Journal of Neurophysiology 87, no. 6 (June 1, 2002): 2770–77. http://dx.doi.org/10.1152/jn.2002.87.6.2770.
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Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.
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Abraham, Wickliffe C., and Joanna M. Williams. "LTP maintenance and its protein synthesis-dependence." Neurobiology of Learning and Memory 89, no. 3 (March 2008): 260–68. http://dx.doi.org/10.1016/j.nlm.2007.10.001.
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Wang, Hai L., Li Y. Tsai, and Eminy H. Y. Lee. "Corticotropin-Releasing Factor Produces a Protein Synthesis–Dependent Long-Lasting Potentiation in Dentate Gyrus Neurons." Journal of Neurophysiology 83, no. 1 (January 1, 2000): 343–49. http://dx.doi.org/10.1152/jn.2000.83.1.343.
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Corticotropin-releasing factor (CRF) was shown to produce a long-lasting potentiation of synaptic efficacy in dentate gyrus neurons of the rat hippocampus in vivo. This potentiation was shown to share some similarities with tetanization-induced long-term potentiation (LTP). In the present study, we further examined the mechanism underlying CRF-induced long-lasting potentiation in rat hippocampus in vivo. Results indicated that the RNA synthesis inhibitor actinomycin-D, at a concentration that did not change basal synaptic transmission alone (5 μg), significantly decreased CRF-induced potentiation. Similarly, the protein synthesis inhibitor emetine, at a concentration that did not affect hippocampal synaptic transmission alone (5 μg), also markedly inhibited CRF-induced potentiation. These results suggest that like the late phase of LTP, CRF-induced long-lasting potentiation also critically depend on protein synthesis. Further, prior maximum excitation of dentate gyrus neurons with tetanization occluded further potentiation of these neurons produced by CRF and vise versa. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed that CRF mRNA level in the dentate gyrus was significantly increased 1 h after LTP recording. Together with our previous findings that CRF antagonist dose-dependently diminishes tetanization-induced LTP, these results suggest that both CRF-induced long-lasting potentiation and tetanization-induced LTP require protein synthesis and that CRF neurons are possibly involved in the neural circuits underlying LTP.
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Maltsev, Alexander V., Natalia V. Bal, and Pavel M. Balaban. "Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase." International Journal of Molecular Sciences 22, no. 9 (May 4, 2021): 4857. http://dx.doi.org/10.3390/ijms22094857.
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Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.
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Chen, Huan-Xin, Mali Jiang, Dilek Akakin, and Steven N. Roper. "Long-Term Potentiation of Excitatory Synapses on Neocortical Somatostatin-Expressing Interneurons." Journal of Neurophysiology 102, no. 6 (December 2009): 3251–59. http://dx.doi.org/10.1152/jn.00641.2009.
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Synaptic plasticity has been extensively studied in principal neurons of the neocortex, but less work has been done on GABAergic interneurons. Interneurons consist of multiple subtypes and their synaptic properties vary between subtypes. In the present study, we have examined long-term potentiation (LTP) of excitatory synapses on somatostatin (SS)-expressing interneurons in neocortex using transgenic mice that express enhanced green fluorescent protein in these interneurons. We found that a strong theta burst stimulation was required to induce LTP in SS interneurons. LTP was associated with a reduction in paired-pulse facilitation and was not blocked by an N-methyl-d-aspartate receptor (NMDAR) antagonist. LTP was not affected by chelating postsynaptic Ca2+ with BAPTA, a fast Ca2+ chelator, and blocking L-type voltage-dependent Ca2+ channels with nimodipine. Application of forskolin, an activator of adenylate cyclase that increases cyclic adenosine monophosphate (cAMP) concentration, enhanced synaptic transmission and occluded subsequent induction of LTP. Finally, we found that LTP was blocked by protein kinase A (PKA) inhibitors. Our results suggest that excitatory synapses on SS interneurons express a presynaptic form of LTP that is not dependent on NMDARs or postsynaptic Ca2+ rise but is dependent on the cAMP–PKA signaling pathway.
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Li, Wei, Xin Xu, and Lucas Pozzo-Miller. "Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors." Proceedings of the National Academy of Sciences 113, no. 11 (February 29, 2016): E1575—E1584. http://dx.doi.org/10.1073/pnas.1517244113.
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Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.
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Hernández, Alejandro, Héctor Burgos, Mauricio Mondaca, Rafael Barra, Héctor Núñez, Hernán Pérez, Rubén Soto-Moyano, et al. "Effect of Prenatal Protein Malnutrition on Long-Term Potentiation and BDNF Protein Expression in the Rat Entorhinal Cortex after Neocortical and Hippocampal Tetanization." Neural Plasticity 2008 (2008): 1–9. http://dx.doi.org/10.1155/2008/646919.
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Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.
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Grover, Lawrence M., and Chen Yan. "Evidence for Involvement of Group II/III Metabotropic Glutamate Receptors in NMDA Receptor–Independent Long-Term Potentiation in Area CA1 of Rat Hippocampus." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 2956–69. http://dx.doi.org/10.1152/jn.1999.82.6.2956.
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Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl-d-aspartate (NMDA) receptor–independent long-term potentiation (LTP) in area CA1 of the rat hippocampus. To learn more about the specific roles played by mGluRs in NMDA receptor–independent LTP, we used whole cell recordings to load individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5′-O-(2-thiodiphosphate), GDPβS]. Although loading postsynaptic CA1 pyramidal neurons with GDPβS significantly reduced G-protein dependent postsynaptic potentials, GDPβS failed to prevent NMDA receptor– independent LTP, suggesting that postsynaptic G-protein–dependent mGluRs are not required. We also performed a series of extracellular field potential experiments in which we applied group-selective mGluR antagonists. We had previously determined that paired-pulse facilitation (PPF) was decreased during the first 30–45 min of NMDA receptor–independent LTP. To determine if mGluRs might be involved in these PPF changes, we used a twin-pulse stimulation protocol to measure PPF in field potential experiments. NMDA receptor–independent LTP was prevented by a group II mGluR antagonist [(2S)-α-ethylglutamic acid] and a group III mGluR antagonist [(RS)-α-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group II and III mGluR antagonists [(RS)-α-methylserine-O-phosphate monophenyl ester or (RS)-α-methylserine-O-phosphate]. NMDA receptor–independent LTP was not prevented by either of the group I mGluR antagonists we examined, (RS)-1-aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The PPF changes which accompany NMDA receptor–independent LTP were not prevented by any of the group-selective mGluR antagonists we examined, even when the LTP itself was blocked. Finally, we found that tetanic stimulation in the presence of group III mGluR antagonists lead to nonspecific potentiation in control (nontetanized) input pathways. Taken together, our results argue against the involvement of postsynaptic group I mGluRs in NMDA receptor–independent LTP. Group II and/or group III mGluRs are required, but the specific details of the roles played by these mGluRs in NMDA receptor–independent LTP are uncertain. Based on the pattern of results we obtained, we suggest that group II mGluRs are required for induction of NMDA receptor–independent LTP, and that group III mGluRs are involved in determining the input specificity of NMDA receptor–independent LTP by suppressing potentiation of nearby, nontetanized synapses.
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John Peter, Arun T., Ngaam J. Cheung, and Benoît Kornmann. "Csf1: A Putative Lipid Transport Protein Required for Homeoviscous Adaptation of the Lipidome." Contact 5 (January 2022): 251525642211019. http://dx.doi.org/10.1177/25152564221101974.
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The non-vesicular transport of lipids between organelles mediated by lipid transport proteins (LTPs) is a key determinant of organelle biogenesis and function. Despite performing a vital function in organelle homeostasis, none of the LTP-encoding genes identified so far are truly essential, even in the simple genome of yeast, suggesting widespread redundancy. In line with this fact, it has been found that a number of LTPs have overlapping functions, making it challenging to assign unique roles for an individual LTP in lipid distribution. In our genetic screens under stringent conditions in which the distinct function of an LTP might become essential, we stumbled upon Csf1, a highly conserved protein with a Chorein-N motif found in other lipid transporters and unraveled a new function for Csf1 in lipid remodeling and homeoviscous adaptation of the lipidome. Here, we further speculate on the potential mechanisms of how the putative function of Csf1 in lipid transport could be intimately connected to its role in lipid remodeling across organelles.
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Sahoo, Biswaranjan, and Shiv K. Sharma. "Sulfotransferase activity contributes to long-term potentiation and long-term memory." Learning & Memory 29, no. 6 (May 19, 2022): 155–59. http://dx.doi.org/10.1101/lm.053538.121.
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A critical role of protein modifications such as phosphorylation and acetylation in synaptic plasticity and memory is well documented. Tyrosine sulfation plays important roles in several biological processes. However, its role in synaptic plasticity and memory is not well understood. Here, we show that sulfation contributes to long-term potentiation (LTP) in the hippocampal slices. In addition, inhibition of sulfation impairs long-term memory in a spatial memory task without affecting acquisition or short-term memory. Furthermore, LTP-inducing stimulus enhances protein tyrosine sulfation. These results suggest an important role for tyrosine sulfation in LTP and memory.
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Wang, Xingxing, Qinfang Shi, Arpit Kumar Pradhan, Laura Ziegon, Martin Schlegel, and Gerhard Rammes. "Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss." International Journal of Molecular Sciences 23, no. 12 (June 14, 2022): 6637. http://dx.doi.org/10.3390/ijms23126637.
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Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ1–42) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippocampal dendritic spine plasticity and BACE-dependent APP processing remain unclear. In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Thereafter, CA1 dendritic spine density, APP processing-related molecule expressions, nectin-3 levels, and long-term potentiation (LTP) were tested. The nectin-3 downregulation on LTP and dendritic spines were evaluated. Sevo treatment increased hippocampal mouse Aβ1–42 (mAβ1–42), abolished CA1-LTP, and decreased spine density and nectin-3 expressions in the CA1 region. Furthermore, CA1-nectin-3 knockdown blocked LTP and reduced spine density. Iso treatment decreased spine density and attenuated LTP. Although Xe blocked LTP, it did not affect spine density, mAβ1–42, or nectin-3. Finally, antagonizing BACE activity partly restored sevo-induced deficits. Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling.
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Scott-McKean, Jonah J., Adriano L. Roque, Krystyna Surewicz, Mark W. Johnson, Witold K. Surewicz, and Alberto C. S. Costa. "Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome." Neural Plasticity 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/9235796.
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The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1 μM memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ≥10 μM picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices.
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Vangelisti, Alberto, Samuel Simoni, Gabriele Usai, Flavia Mascagni, Maria Ventimiglia, Lucia Natali, Andrea Cavallini, and Tommaso Giordani. "In Silico Genome-Wide Characterisation of the Lipid Transfer Protein Multigenic Family in Sunflower (H. annuus L.)." Plants 11, no. 5 (February 28, 2022): 664. http://dx.doi.org/10.3390/plants11050664.
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The sunflower (Helianthus annuus L.) is among the most widely cultivated crops in the world due to the oilseed production. Lipid transfer proteins (LTPs) are low molecular mass proteins encoded by a broad multigenic family in higher plants, showing a vast range of functions; these proteins have not been characterised in sunflower at the genomic level. In this work, we exploited the reliable genome sequence of sunflower to identify and characterise the LTP multigenic family in H. annuus. Overall, 101 sunflower putative LTP genes were identified using a homology search and the HMM algorithm. The selected sequences were characterised through phylogenetic analysis, exon–intron organisation, and protein structural motifs. Sunflower LTPs were subdivided into four clades, reflecting their genomic and structural organisation. This gene family was further investigated by analysing the possible duplication origin of genes, which showed the prevalence of tandem and whole genome duplication events, a result that is in line with polyploidisation events that occurred during sunflower genome evolution. Furthermore, LTP gene expression was evaluated on cDNA libraries constructed on six sunflower tissues (leaf, root, ligule, seed, stamen, and pistil) and from roots treated with stimuli mimicking biotic and abiotic stress. Genes encoding LTPs belonging to three out of four clades responded specifically to external stimuli, especially to abscisic acid, auxin, and the saline environment. Interestingly, genes encoding proteins belonging to one clade were expressed exclusively in sunflower seeds. This work is a first attempt of genome-wide identification and characterisation of the LTP multigenic family in a plant species.
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Bramham, Clive R. "Molecular mechanisms of synaptic consolidation during sleep: BDNF function and dendritic protein synthesis." Behavioral and Brain Sciences 28, no. 1 (February 2005): 65–66. http://dx.doi.org/10.1017/s0140525x05230029.
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Insights into the role of sleep in the molecular mechanisms of memory consolidation may come from studies of activity-dependent synaptic plasticity, such as long-term potentiation (LTP). This commentary posits a specific contribution of sleep to LTP stabilization, in which mRNA transported to dendrites during wakefulness is translated during sleep. Brain-derived neurotrophic factor may drive the translation of newly transported and resident mRNA.
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Stanton, P. K., and A. T. Gage. "Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression." Journal of Neurophysiology 76, no. 3 (September 1, 1996): 2097–101. http://dx.doi.org/10.1152/jn.1996.76.3.2097.
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1. Extracellular bath application of the selective Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 to hippocampal slices in vitro blocked the induction of long-term depression (LTD) by low-frequency Schaffer collateral stimulation (1 Hz/15 min) of the same concentration as has been shown previously to prevent induction of long-term potentiation (LTP) at these synapses. 2. In contrast, postsynaptic intracellular infusion of KN-62 into single CA1 pyramidal neurons did not prevent induction of LTD, although it was quite effective in blocking LTP. 3. We conclude that there is a presynaptic CaMKII that must be activated to induce LTD, whereas postsynaptic CaMKII stimulation is needed to evoke LTP. 4. Bath application of KN-62 also blocked depotentiation by low-frequency stimuli of previously induced LTP, suggesting that induction of depotentiation and de novo LTD may require the same CaMKII-dependent mechanisms.
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Kim, Seonil, Roseann F. Titcombe, Hong Zhang, Latika Khatri, Hiwot K. Girma, Franz Hofmann, Ottavio Arancio, and Edward B. Ziff. "Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors." Proceedings of the National Academy of Sciences 112, no. 10 (February 23, 2015): 3122–27. http://dx.doi.org/10.1073/pnas.1417498112.
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Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca2+-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca2+-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.
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Diz, Mariângela S. S., André O. Carvalho, and Valdirene M. Gomes. "Purification and molecular mass determination of a lipid transfer protein exuded from Vigna unguiculata seeds." Brazilian Journal of Plant Physiology 15, no. 3 (December 2003): 171–75. http://dx.doi.org/10.1590/s1677-04202003000300007.
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Plants exude a variety of substances through their surface especially of roots and germinating seeds. Some of these released compounds seem to have an inhibitory action against certain pathogens. Lipid transfer proteins (LTPs) are 9 kDa cysteine-rich cationic peptides and are thought to play a role in the protection of plants against microbial infections. The aim of this work was to isolate and determine the molecular mass of a LTP present in the exudates of imbibed cowpea seeds. For exudation induction, 50 seeds were submerged in 50 mL sterile 100 mmol.L-1 Na-acetate buffer, pH 4.5 and shaken at 30 ºC for 24 h. The resulting exudate was subjected to ammonium sulphate fractionation and the pellet formed between 0 and 70 % saturation was dialysed and recovered by freeze drying. Further purification steps were carried out using chromatographic methods and the molecular mass of the LTP determined. All of these steps were monitored by SDS-Tricine gel electrophoresis and Western blotting using an anti-LTP serum. The purified LTP showed a relative molecular mass of 9 kDa.
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KORZ, VOLKER, and JULIETTA U. FREY. "Emotional and cognitive reinforcement of rat hippocampal long-term potentiation by different learning paradigms." Neuron Glia Biology 1, no. 3 (August 2004): 253–61. http://dx.doi.org/10.1017/s1740925x05000153.
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In earlier studies we have shown that a protein-synthesis-independent, early, long-term potentiaton (early-LTP) that lasts up to 4–5 hours can be transformed (reinforced) into a protein-synthesis-dependent late-LTP that lasts ≥8 hours by either an emotional challenge (e.g. swim stress) or mastering a cognitive task (e.g. spatial learning). In the present study we show that LTP-reinforcement by spatial training depends on the specific constraints of the learning paradigm. In a holeboard paradigm, LTP-reinforcement is related to the formation of a lasting reference memory whereas water-maze training gives more heterogenous results. Thus, cognitive aspects interfere with emotionally challenging components of the latter paradigm. These data indicate that different spatial-learning tasks are weighted distinctly by the animal. Thus, we show that aspects of specific spatial-learning paradigms such as shifts of attention and emotional content directly influence functional plasticity and memory formation.
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Sandkühler, J. "CS03-01 - Learning and memory in pain pathways." European Psychiatry 26, S2 (March 2011): 1774. http://dx.doi.org/10.1016/s0924-9338(11)73478-2.
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Hyperalgesia frequently results from injuries or inflammation of peripheral tissues, including nervous tissue and paradoxically also from the treatment with μ-opioid receptor agonists. Compelling evidence indicates that signal amplification in central pain pathways plays an important role for the maintenance of hyperalgesia1. In superficial spinal dorsal horn synaptic transmission between nociceptive C-fibres and lamina I projection neurons can be potentiated for prolonged periods of time in an activity dependent manner. These forms of synaptic long-term potentiation (LTP) can be securely prevented when opioids are applied during afferent stimulation. The blockage of LTP induction by opioids is a likely mechanism or pre-emptive analgesia. Upon withdrawal from high doses of opioids, however, LTP may develop at C-fibre synapses. During the latter form of LTP induction presynaptic activity at C-fibres is depressed rather than enhanced. Despite these fundamental differences in the induction, activity dependent- and opioidergic LTP share signalling pathways. This includes the activation of NMDA receptors, the rise in postsynaptic Ca2+ concentration and the activation of protein kinase C. Induction of opioidergic LTP further requires postsynaptic G-protein coupling which is in contrast to the presynaptic inhibition by opioids. LTP induction is abolished by blocking the Ca2+ rise upon withdrawal from the opioids. It is likely that the potentiation in synaptic strength translates into enhanced pain behaviour1. Plasticity at the first synapse in pain pathways is a promising target for the prevention and treatment of hyperalgesia of various origins.
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Feldmann, Le Prieult, Felzen, Thal, Engelhard, Behl, and Mittmann. "Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice." International Journal of Molecular Sciences 20, no. 12 (June 21, 2019): 3048. http://dx.doi.org/10.3390/ijms20123048.
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Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation.The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity ofthe lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucialfor synaptic long-term plasticity including the protein degradation systems, proteasome andautophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity andprotein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in themotor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) wasinduced by theta-burst stimulation in acute brain slices after survival times of 1–2 days. Proteinlevels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII)was quantified by Western blots, and the protein degradation activity by enzymatical assays. Weobserved missing maintenance of l-LTP in the ipsilateral hemisphere, however not in thecontralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly,the protein degradation revealed bidirectional changes with a reduced proteasome activity and anincreased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence ofpharmacologically modified protein degradation systems also led to an impaired synaptic plasticity:bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, bothadministered during theta burst stimulation, blocked the induction of LTP. These data indicate thatalterations in protein degradation pathways likely contribute to cognitive deficits in the acute phaseafter TBI, which could be interesting for future approaches towards neuroprotective treatmentsearly after traumatic brain injury.
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Okamoto, Kenichi, Miquel Bosch, and Yasunori Hayashi. "The Roles of CaMKII and F-Actin in the Structural Plasticity of Dendritic Spines: A Potential Molecular Identity of a Synaptic Tag?" Physiology 24, no. 6 (December 2009): 357–66. http://dx.doi.org/10.1152/physiol.00029.2009.
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Ca2+/calmodulin-dependent protein kinase II (CaMKII) and actin are two crucial molecules involved in long-term potentiation (LTP). In addition to its signaling function, CaMKII plays a structural role via direct interaction with actin filaments, thus coupling functional and structural plasticity in dendritic spines. The status of F-actin, regulated by CaMKII, determines the postsynaptic protein binding capacity and thus may act as a synaptic tag that consolidates LTP.
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Bramham, Clive R. "Local protein synthesis, actin dynamics, and LTP consolidation." Current Opinion in Neurobiology 18, no. 5 (October 2008): 524–31. http://dx.doi.org/10.1016/j.conb.2008.09.013.
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Boehm, J., and R. Malinow. "AMPA receptor phosphorylation during synaptic plasticity." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1354–56. http://dx.doi.org/10.1042/bst0331354.
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A widely studied example of vertebrate plasticity is LTP (long-term potentiation), the persistent synaptic enhancement that follows a brief period of coinciding pre- and post-synaptic activity. During LTP, different kinases, including CaMKII (calcium/calmodulin-dependent protein kinase II) and protein kinase A, become activated and play critical roles in induction and maintenance of enhanced transmission. Biochemical analyses have revealed several regulated phosphorylation sites in the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits, GluR1 and GluR4. The regulated insertion of these receptors is a key event in the induction of LTP. Here, we discuss the phosphorylation of GluR1 and GluR4 and its role in receptor delivery and neuronal plasticity.
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Wu, Jianqun, Michael J. Rowan, and Roger Anwyl. "Long-Term Potentiation Is Mediated by Multiple Kinase Cascades Involving CaMKII or Either PKA or p42/44 MAPK in the Adult Rat Dentate Gyrus In Vitro." Journal of Neurophysiology 95, no. 6 (June 2006): 3519–27. http://dx.doi.org/10.1152/jn.01235.2005.
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The induction of NMDA-receptor–dependent long-term potentiation (LTP) in adult CA1 is contingent on activation of Ca/calmodulin-dependent protein kinase II (CaMKII). However, little is known about kinase mediation of LTP in the dentate gyrus. In the present study, the involvement of the kinases CaMKII, PKA, and MAPK in the induction of LTP was studied in the dentate gyrus of adult rats. Individual application of selective inhibitors of CaMKII, MEK, or PKA did not inhibit induction of LTP. In contrast, coapplication of a CaMKII inhibitor with either a PKA or MEK inhibitor resulted in a strong block of LTP. Induction of LTP was blocked by the coapplication of the inhibitors CaMKII and PKA or MEK, both when they were applied 1 h before the induction stimulus and also when they were applied after the induction stimulus. Thus LTP is mediated by either of two parallel cascades, one involving CaMKII and the other PKA or MAPK. Moreover, these cascades are active for a certain period after the induction stimulus.
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Gough, Nancy R. "Translating Memories." Science Signaling 6, no. 273 (April 30, 2013): ec94-ec94. http://dx.doi.org/10.1126/scisignal.2004279.
Full textAbstract:
The cellular model of memory is a synaptic plasticity event called long-term potentiation (LTP). LTP can be divided into two phases: The early phase (E-LTP) lasts less than 2 hours and does not require new protein synthesis, and the late phase (L-LTP) can last many hours and requires new protein synthesis. Translation of mRNAs is regulated through various mechanisms, one of which is the binding of poly(A)-binding protein (PABP) to the poly(A) tail of the target mRNA. PAIP2A and PAIP2B (PAIP-interacting protein 2A and 2B) inhibit translation by interfering with PABP function. Khoutorsky et al. found that degradation of PAIP2A, which is the form that is abundant in the brain, linked synaptic activity to enhanced translation and contributed to learning and memory in mice. Hippocampal slices from Paip2a–/– mice showed L-LTP in response to a stimulus that only triggered E-LTP in slices from wild-type mice and showed impaired L-LTP in response to a stimulus that triggered L-LTP in slices from wild-type mice. Consistent with these electrophysiological studies, behavorial memory tests indicated that Paip2a–/– mice showed faster learning in spatial long-term memory tests in response to weak training but showed impaired learning in response to a long-term contextual fear conditioning test that used a strong training paradigm. Experiments with cultured neurons and hippocampal slices showed an activity-dependent decrease in the abundance of PAIP2A that could be prevented by pharmacological inhibition of the calcium-dependent proteases calpains. The calpain-dependent reduction in PAIP2A was also detected in mice subjected to the contextual fear conditioning paradigm, and infusion of calpain inhibitors impaired long-term contextual fear memory. Increased production of calcium-calmodulin kinase IIα (CaMKIIα) occurs in response to synaptic activity and is necessary for learning. The abundance of CaMKIIα in the hippocampus was increased in Paip2a–/– mice trained in a contextual fear conditioning paradigm compared with untrained mice or wild-type trained mice. This increase in CaMKIIα resulted from increased translation because CaMKIIα mRNA was shifted to heavy polysome fractions in the brains of Paip2a–/– trained mice and the association of PABP with this mRNA was greatest in the Paip2a–/– trained mice. Thus, activity-dependent degradation of a translation inhibitor contributes to the enhanced translation needed for learning and memory.A. Khoutorsky, A, Yanagiya, C. G. Gkogkas, M. R. Fabian, M. Prager-Khoutorsky, R. Cao, K. Gamache, F. Bouthiette, A. Parsyan, R. E. Sorge, J. S. Mogil, K. Nader, J.-C. Lacaille, N. Sonenberg, Control of synaptic plasticity and memory via suppression of poly(A)-binding protein. Neuron78, 298–311 (2013). [Online Journal]
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Duda, Przemysław, Tomasz Wójtowicz, Jakub Janczara, Daniel Krowarsch, Aleksandra Czyrek, Agnieszka Gizak, and Dariusz Rakus. "Fructose 1,6-Bisphosphatase 2 Plays a Crucial Role in the Induction and Maintenance of Long-Term Potentiation." Cells 9, no. 6 (June 1, 2020): 1375. http://dx.doi.org/10.3390/cells9061375.
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Long-term potentiation (LTP) is a molecular basis of memory formation. Here, we demonstrate that LTP critically depends on fructose 1,6-bisphosphatase 2 (Fbp2)—a glyconeogenic enzyme and moonlighting protein protecting mitochondria against stress. We show that LTP induction regulates Fbp2 association with neuronal mitochondria and Camk2 and that the Fbp2–Camk2 interaction correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme with a synthetic effector mimicking the action of physiological inhibitors (NAD+ and AMP) abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late phase LTP markers. Astrocyte-derived lactate reduces NAD+/NADH ratio in neurons and thus diminishes the pool of tetrameric and increases the fraction of dimeric Fbp2. We therefore hypothesize that this NAD+-level-dependent increase of the Fbp2 dimer/tetramer ratio might be a crucial mechanism in which astrocyte–neuron lactate shuttle stimulates LTP formation.
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Cavus, I., and T. Teyler. "Two forms of long-term potentiation in area CA1 activate different signal transduction cascades." Journal of Neurophysiology 76, no. 5 (November 1, 1996): 3038–47. http://dx.doi.org/10.1152/jn.1996.76.5.3038.
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1. The effects of protein kinase inhibitors on N-methyl-D-aspartate (NMDA)-receptor-mediated, voltage-dependent calcium channel (VDCC)-mediated, and 100-Hz long-term potentiation (LTP) were studied in area CA1 of rat hippocampal slices. 2. A 25-Hz tetanus induced a quickly developing potentiation that was blocked by the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV) and was not affected by the L-type VDCC inhibitor nifedipine, suggesting that it was mediated by NMDA receptors (NMDA-LTP). 3. Application of a 200-Hz tetanus in APV induced a slowly developing NMDA-receptor-independent potentiation that was blocked by nifedipine and thus named VDCC-LTP. NMDA- and VDCC-LTP reached comparable magnitudes despite their different induction parameters and developmental kinetics. 4. Bath perfusion of the broad-spectrum serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) blocked NMDA-LTP but not VDCC-LTP, whereas the tyrosine kinase inhibitors genistein and lavendustin A blocked VDCC-LTP but not NMDA-LTP. These results suggest a differential involvement of H-7-sensitive serine/threonine kinases and tyrosine kinases in the two forms of LTP. 5. Tetanization of 200 Hz in control media resulted in a compound potentiation twice as large as NMDA- or VDCC-LTP, implying that the two forms of LTP did not facilitate or reduce each other's expression. The often-used 100-Hz tetanus (1 s twice) induced a potentiation that was comparable in size with the 200-Hz compound LTP. Nifedipine, genistein, and lavendustin A reduced the 100-Hz LTP by approximately 50%, suggesting that this LTP is also a compound potentiation consisting of NMDA- and VDCC-mediated components and their corresponding signal transduction pathways.
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Wang, Ning, Linlin Chen, Nan Cheng, Jingyun Zhang, Tian Tian, and Wei Lu. "Active Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Regulates NMDA Receptor Mediated Postischemic Long-Term Potentiation (i-LTP) by Promoting the Interaction between CaMKII and NMDA Receptors in Ischemia." Neural Plasticity 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/827161.
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Active calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to take a critical role in the induction of long-term potentiation (LTP). Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR)-mediated postischemic long-term potentiation (NMDA i-LTP). Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs) at different time points following ischemia onsetin vitrooxygen and glucose deprivation (OGD) ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min) or longer (25 min) OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia bothin vitroOGD orin vivophotothrombotic lesion (PT) models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.
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Patel, Hamish, and Reza Zamani. "The role of PKMζ in the maintenance of long-term memory: a review." Reviews in the Neurosciences 32, no. 5 (February 8, 2021): 481–94. http://dx.doi.org/10.1515/revneuro-2020-0105.
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Abstract Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.