scholarly journals Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain

2021 ◽  
Vol 22 (23) ◽  
pp. 12779
Author(s):  
Anna Tyrtyshnaia ◽  
Anatoly Bondar ◽  
Sophia Konovalova ◽  
Igor Manzhulo
Keyword(s):  
Neuropathic Pain ◽  
Beneficial Effect ◽  
Pain Treatment ◽  
Dendritic Tree ◽  
Long Term Potentiation ◽  
Receptor Expression ◽  
Integrative Approach ◽  
Long Term Memory ◽  
Hippocampal Plasticity

Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain.

Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons

2019 ◽  
Vol 208 (3-4) ◽  
pp. 89-100 ◽  
Author(s):  
Anna A. Tyrtyshnaia ◽  
Igor V. Manzhulo ◽  
Sophia P. Konovalova ◽  
Anna A. Zagliadkina
Keyword(s):  
Neuropathic Pain ◽  
Cognitive Impairment ◽  
Pyramidal Neurons ◽  
Dendritic Tree ◽  
Long Term Memory ◽  
Chronic Neuropathic Pain ◽  
Term Memory ◽  
Hippocampal Area ◽  
Ca3 Pyramidal Neurons

The International Pain Association defines neuropathic pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Recent studies show that chronic neuropathic pain causes both morphological and functional changes within brain structures. Due to the impact of supraspinal centers on pain signal processing, patients with chronic pain often suffer from depression, anxiety, memory impairment, and learning disabilities. Changes in hippocampal neuronal and glial plasticity can play a substantial role in the development of these symptoms. Given the special role of the CA3 hippocampal area in chronic stress reactions, we suggested that this region may undergo significant morphological changes as a result of persistent pain. Since the CA3 area is involved in the implementation of hippocampus-dependent memory, changes in the neuronal morphology can cause cognitive impairment observed in chronic neuropathic pain. This study aimed to elucidate the structural and plastic changes within the hippocampus associated with dendritic tree atrophy of CA3 pyramidal neurons in mice with chronic sciatic nerve constriction. Behavioral testing revealed impaired working and long-term memory in mice with a chronic constriction injury. Using the Golgi-Cox method, we revealed a decrease in the number of branches and dendritic length of CA3 pyramidal neurons. The dendritic spine number was decreased, predominantly due to a reduction in mushroom spines. An ­immunohistochemical study showed changes in astro- and microglial activity, which could affect the morphology of neurons both directly and indirectly via the regulation of neurotrophic factor synthesis. Using ELISA, we found a decrease in brain-derived neurotrophic factor production and an increase in neurotrophin-3 production. Morphological and biochemical changes in the CA3 area are accompanied by impaired working and long-term memory of animals. Thus, we can conclude that morphological and biochemical changes within the CA3 hippocampal area may underlie the cognitive impairment in neuropathic pain.

The role of PKMζ in the maintenance of long-term memory: a review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hamish Patel ◽  
Reza Zamani
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Long Term Potentiation ◽  
Global Memory ◽  
Long Term Memory ◽  
Compensatory Mechanism ◽  
Term Memory ◽  
Kinase C

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.

scholarly journals Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

2019 ◽  
Vol 4 (40) ◽  
pp. eaay5199 ◽  
Author(s):  
Miguel Ribeiro ◽  
Helena C. Brigas ◽  
Mariana Temido-Ferreira ◽  
Paula A. Pousinha ◽  
Tommy Regen ◽  
...  
Keyword(s):  
T Cell ◽  
Short Term Memory ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Interleukin 17 ◽  
Γδ T Cell ◽  
Short Term ◽  
Functional Link ◽  
Term Memory

The notion of “immune privilege” of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here, we show that noninflammatory interleukin-17 (IL-17) derived from a previously unknown fetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory while retaining long-term memory. The plasticity of glutamatergic synapses was reduced in the absence of IL-17, resulting in impaired long-term potentiation in the hippocampus. Conversely, IL-17 enhanced glial cell production of brain-derived neurotropic factor, whose exogenous provision rescued the synaptic and behavioral phenotypes of IL-17–deficient animals. Together, our work provides previously unknown clues on the mechanisms that regulate short-term versus long-term memory and on the evolutionary and functional link between the immune and nervous systems.

scholarly journals Neuro-Transistor Based on UV-Treated Charge Trapping in MoTe2 for Artificial Synaptic Features

Nanomaterials ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2326
Author(s):  
Shania Rehman ◽  
Muhammad Farooq Khan ◽  
Mehr Khalid Rahmani ◽  
Honggyun Kim ◽  
Harshada Patil ◽  
...  
Keyword(s):  
Field Effect Transistors ◽  
Charge Trapping ◽  
Long Term Potentiation ◽  
Spike Timing ◽  
Long Term Memory ◽  
Ambient Conditions ◽  
Time Constants ◽  
Brain Functions ◽  
Gate Pulse

The diversity of brain functions depend on the release of neurotransmitters in chemical synapses. The back gated three terminal field effect transistors (FETs) are auspicious candidates for the emulation of biological functions to recognize the proficient neuromorphic computing systems. In order to encourage the hysteresis loops, we treated the bottom side of MoTe2 flake with deep ultraviolet light in ambient conditions. Here, we modulate the short-term and long-term memory effects due to the trapping and de-trapping of electron events in few layers of a MoTe2 transistor. However, MoTe2 FETs are investigated to reveal the time constants of electron trapping/de-trapping while applying the gate-voltage pulses. Our devices exploit the hysteresis effect in the transfer curves of MoTe2 FETs to explore the excitatory/inhibitory post-synaptic currents (EPSC/IPSC), long-term potentiation (LTP), long-term depression (LTD), spike timing/amplitude-dependent plasticity (STDP/SADP), and paired pulse facilitation (PPF). Further, the time constants for potentiation and depression is found to be 0.6 and 0.9 s, respectively which seems plausible for biological synapses. In addition, the change of synaptic weight in MoTe2 conductance is found to be 41% at negative gate pulse and 38% for positive gate pulse, respectively. Our findings can provide an essential role in the advancement of smart neuromorphic electronics.

scholarly journals Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain

2019 ◽  
Vol 20 (7) ◽  
pp. 1757 ◽  
Author(s):  
Serena Boccella ◽  
Ida Marabese ◽  
Monica Iannotta ◽  
Carmela Belardo ◽  
Volker Neugebauer ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Neuroprotective Effect ◽  
Long Term Potentiation ◽  
Receptor Subtypes ◽  
Cognitive Behavior ◽  
Metabotropic Glutamate ◽  
Beneficial Effects

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain.

scholarly journals ALCAM is involved in spinal long-term potentiation and neuropathic pain

IBRO Reports ◽  
2019 ◽  
Vol 6 ◽  
pp. S287
Author(s):  
Dong-Ho Youn ◽  
Eun-Sung Park ◽  
Aram Kwon ◽  
Sang-Min Jeon ◽  
Ki Bum Park ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Long Term Potentiation ◽  
Term Potentiation

scholarly journals Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules

2017 ◽  
Vol 372 (1715) ◽  
pp. 20160328 ◽  
Author(s):  
Kang K. L. Liu ◽  
Michael F. Hagan ◽  
John E. Lisman
Keyword(s):  
Functional Module ◽  
Late Phase ◽  
Matrix Material ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Information Storage ◽  
Homeostatic Plasticity ◽  
Memory Storage ◽  
Long Term Memory

Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using super-resolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

scholarly journals Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice

2016 ◽  
Vol 311 (1) ◽  
pp. R166-R178 ◽  
Author(s):  
Bruce C. Kennedy ◽  
Jiva G. Dimova ◽  
Srikanth Dakoji ◽  
Li-Lian Yuan ◽  
Jonathan C. Gewirtz ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Pathway Analysis ◽  
Transmembrane Protein ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Molecular Networks ◽  
Long Term Memory ◽  
Term Memory ◽  
Term Potentiation

The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-d-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry.

How the Shape of Pre- and Postsynaptic Signals Can Influence STDP: A Biophysical Model

2004 ◽  
Vol 16 (3) ◽  
pp. 595-625 ◽  
Author(s):  
Ausra Saudargiene ◽  
Bernd Porr ◽  
Florentin Wörgötter
Keyword(s):  
Membrane Potential ◽  
Weight Change ◽  
Hebbian Learning ◽  
Dendritic Tree ◽  
Learning Rule ◽  
Long Term Potentiation ◽  
Spike Timing ◽  
Biophysical Model ◽  
Nmda Channel

Spike-timing-dependent plasticity (STDP) is described by long-term potentiation (LTP), when a presynaptic event precedes a postsynaptic event, and by long-term depression (LTD), when the temporal order is reversed. In this article, we present a biophysical model of STDP based on a differential Hebbian learning rule (ISO learning). This rule correlates presynaptically the NMDA channel conductance with the derivative of the membrane potential at the synapse as the postsynaptic signal. The model is able to reproduce the generic STDP weight change characteristic. We find that (1) The actual shape of the weight change curve strongly depends on the NMDA channel characteristics and on the shape of the membrane potential at the synapse. (2) The typical antisymmetrical STDP curve (LTD and LTP) can become similar to a standard Hebbian characteristic (LTP only) without having to change the learning rule. This occurs if the membrane depolarization has a shallow onset and is long lasting. (3) It is known that the membrane potential varies along the dendrite as a result of the active or passive backpropagation of somatic spikes or because of local dendritic processes. As a consequence, our model predicts that learning properties will be different at different locations on the dendritic tree. In conclusion, such site-specific synaptic plasticity would provide a neuron with powerful learning capabilities.

scholarly journals Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation

2008 ◽  
Vol 294 (2) ◽  
pp. C503-C515 ◽  
Author(s):  
Paul Smolen ◽  
Douglas A. Baxter ◽  
John H. Byrne
Keyword(s):  
Map Kinase ◽  
Dendritic Spine ◽  
Mapk Pathway ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Stable States ◽  
Mapk Activity ◽  
Stochastic Fluctuations ◽  
Term Potentiation

Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (Markevich NI, Hoek JB, Kholodenko BN. J Cell Biol 164: 353–359, 2004) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability was present only within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive-feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations and to parameter variations. Bistability was robust for molecule numbers plausible for a dendritic spine volume. The upper state of MAPK activity was resistant to inhibition of MEK activation for >1 h, which suggests that inhibitor experiments have not sufficed to rule out a role for persistent MAPK activity in the maintenance of long-term potentiation (LTP). These simulations suggest that persistent MAPK activity and consequent upregulation of translation may contribute to LTP maintenance and to long-term memory. Experiments using a fluorescent MAPK substrate may further test this hypothesis.

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