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Understanding LTP in pain pathways
Jürgen Sandkühler
Molecular Pain , 2007, DOI: 10.1186/1744-8069-3-9
Abstract: Long-term potentiation (LTP) is a much studied cellular model of synaptic plasticity. It is generally defined as the long-lasting but not necessarily irreversible increase in synaptic strength [1,2]. At least two different stages of LTP can be distinguished depending upon its duration and the signal transduction pathways involved. Early phase LTP is independent of de-novo protein synthesis and lasts for up to three hours. Late phase LTP involves protein synthesis and lasts longer than three hours, up to the life span of an animal and may involve structural changes at synapses [3]. Short-term potentiation of synaptic strength lasts less than half an hour. Synaptic strength is the magnitude of the post-synaptic response (i.e. the post-synaptic potential or the post-synaptic current, but not action potential firing, see below) in response to a pre-synaptic action potential. LTP can be expressed pre- and/or postsynaptically, i.e. synaptic strength can increase if the release of neurotransmitter(s) is enhanced and/or if the postsynaptic effects of the neurotransmitter(s) become stronger [4]. LTP at synapses in hippocampus is the prime model for learning and memory formation [1]. Recent studies have shown that LTP can also be induced in pain pathways and may contribute to hyperalgesia caused by inflammation, trauma or neuropathy. This review deals with the latter form of LTP."Central sensitisation" is used in the literature in at least two mutually exclusive definitions. Some of the authors use "central sensitisation" as an umbrella term for all forms of changes within the central nervous system which ultimately lead to enhanced pain perception. If using this definition of "central sensitisation" one should keep in mind that none of the presently known phenomena in the central nervous system (CNS) which can be observed in experimental or clinical models of hyperalgesia or allodynia has a proven, causative role for the perception of pain. Thus, all presently proposed mecha
EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers  [PDF]
Lina M. Vargas, Nancy Leal, Lisbell D. Estrada, Adrian González, Felipe Serrano, Katherine Araya, Katia Gysling, Nibaldo C. Inestrosa, Elena B. Pasquale, Alejandra R. Alvarez
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092309
Abstract: The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.
NF-κB p50 subunit knockout impairs late LTP and alters long term memory in the mouse hippocampus
Kensuke Oikawa, Gary L Odero, Eric Platt, Melanie Neuendorff, Avril Hatherell, Michael J Bernstein, Benedict C Albensi
BMC Neuroscience , 2012, DOI: 10.1186/1471-2202-13-45
Abstract: We found that the lack of the NF-κB p50 subunit led to significant decreases in late LTP and in selective but significant alterations in MWM tests (i.e., some improvements during acquisition, but deficits during retention).These results support the hypothesis that the NF-κ p50 subunit is required in long term spatial memory in the hippocampus.A growing body of literature supports a role for NF-κB in synaptic plasticity and memory [1-10]. Long term potentiation (LTP), a paradigm used to measure synaptic function and a molecular correlate of memory, along with behavioral tests of memory, are routinely used to assess hippocampal-dependent alterations in synaptic plasticity and memory [11-19]. Early evidence to support NF-κB’s expression following hippocampal LTP, was discovered in rats in vivo[2]. Also, in the Crab, Chasmagnathus, κB-like DNA-binding activity was found enhanced after long term habitation [20]. In addition, Albensi and Mattson [5] showed impairments in mouse hippocampal LTP when NF-κB activity was blocked with κB decoy DNA. Yeh et al. [21] also showed that histone deacetylase (HDAC) inhibitors enhanced long term memory in the rat amygdala and that these effects could be attenuated with κB decoy DNA administration.The use of specific knockout mice has allowed further clarification concerning NF-κB’s role in memory, although little work has been accomplished along these lines in spite of the importance. For example, Kassed et al [3] demonstrated that lack of the NF-κB p50 subunit (p50?/?) impaired memory in an in vivo active avoidance paradigm. In a later study by Kassed and colleagues [22], NF-κB p50?/? mice also showed reduced anxiety-like behaviors in open field and elevated plus maze experiments. More recently, Denis-Donini et al. [6] demonstrated selective defects in short-term spatial memory performance in p50?/? mice in a Y maze, but without impairment of long-term spatial memory using the Morris water maze (MWM). However, studies in 2010 by Lehman
The roles of STP and LTP in synaptic encoding
Arturas Volianskis,Graham L. Collingridge,Morten S. Jensen
PeerJ , 2013, DOI: 10.7717/peerj.3
Abstract: Long-term potentiation (LTP), a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP) that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.
mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion  [PDF]
Chris P. Jew, Chia-Shan Wu, Hao Sun, Jie Zhu, Jui-Yen Huang, Dinghui Yu, Nicholas J. Justice, Hui-Chen Lu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070415
Abstract: The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions.
Temporal Sensitivity of Protein Kinase A Activation in Late-Phase Long Term Potentiation  [PDF]
MyungSook Kim,Ted Huang,Ted Abel,Kim T. Blackwell
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000691
Abstract: Protein kinases play critical roles in learning and memory and in long term potentiation (LTP), a form of synaptic plasticity. The induction of late-phase LTP (L-LTP) in the CA1 region of the hippocampus requires several kinases, including CaMKII and PKA, which are activated by calcium-dependent signaling processes and other intracellular signaling pathways. The requirement for PKA is limited to L-LTP induced using spaced stimuli, but not massed stimuli. To investigate this temporal sensitivity of PKA, a computational biochemical model of L-LTP induction in CA1 pyramidal neurons was developed. The model describes the interactions of calcium and cAMP signaling pathways and is based on published biochemical measurements of two key synaptic signaling molecules, PKA and CaMKII. The model is stimulated using four 100 Hz tetani separated by 3 sec (massed) or 300 sec (spaced), identical to experimental L-LTP induction protocols. Simulations show that spaced stimulation activates more PKA than massed stimulation, and makes a key experimental prediction, that L-LTP is PKA-dependent for intervals larger than 60 sec. Experimental measurements of L-LTP demonstrate that intervals of 80 sec, but not 40 sec, produce PKA-dependent L-LTP, thereby confirming the model prediction. Examination of CaMKII reveals that its temporal sensitivity is opposite that of PKA, suggesting that PKA is required after spaced stimulation to compensate for a decrease in CaMKII. In addition to explaining the temporal sensitivity of PKA, these simulations suggest that the use of several kinases for memory storage allows each to respond optimally to different temporal patterns.
Positive Allosteric Modulators of Type 5 Metabotropic Glutamate Receptors (mGluR5) and Their Therapeutic Potential for the Treatment of CNS Disorders  [PDF]
Richard M. Cleva,M. Foster Olive
Molecules , 2011, DOI: 10.3390/molecules16032097
Abstract: Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
Fluoride and Arsenic Exposure Impairs Learning and Memory and Decreases mGluR5 Expression in the Hippocampus and Cortex in Rats  [PDF]
Shoufang Jiang, Jing Su, Sanqiao Yao, Yanshu Zhang, Fuyuan Cao, Fei Wang, Huihui Wang, Jun Li, Shuhua Xi
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096041
Abstract: Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.
Hypo-Anxious Phenotype of Adolescent Offspring Prenatally Exposed to LPS Is Associated with Reduced mGluR5 Expression in Hippocampus  [PDF]
Dany Arsenault, Aijun Zhu, Chunyu Gong, Kun-Eek Kil, Sreekanth Kura, Ji-Kyung Choi, Anna-Liisa Brownell
Open Journal of Medical Psychology (OJMP) , 2014, DOI: 10.4236/ojmp.2014.33022
Abstract: Many studies have reported long-term modulation of metabotropic glutamate receptor 5 (mGluR5) by inflammatory processes and a pharmacological modulation of mGluR5 is known to regulate anxiety level. However, it is not known if non-pharmacological modulation of mGluR5 by inflammation impaired the unconditional level of anxiety. In this study, we investigated this relation in LPS prenatal immune challenge (120 μg/kg, 3x i.p. injection in late gestation), a developmental model of neuroinflammation in which some studies have reported hypo-anxious phenotype. Using positron emission tomographic imaging (PET) approaches, we have demonstrated a decrease in the binding potential of [18F]fluoro-5-(2-pyridinylethynyl)benzonitrile([18F]FPEB, a radioligand for mGluR5) in hippocampus of adolescent offspring prenatally exposed to LPS, without significant change in the binding of [11C]peripheral benzodiazepine receptor 28 ([11C]PBR28), an inflammatory marker. In addition, dark-light box emergence test revealed a lower level of anxiety in LPS-exposed offspring and this behavioural phenotype was associated with the binding potential of [18F]FPEB in hippocampus. These results confirm that neuroinflammation during developmental phase modulates the physiology of mGluR5 and this alteration can be associated with behavioural phenotype related to anxiety. In addition, this study supports a hypotheses that mGluR5 could be used as a diagnostic target in anxiety.
Long-Lasting LTP Requires Neither Repeated Trains for Its Induction Nor Protein Synthesis for Its Development  [PDF]
Agnès Villers, Emile Godaux, Laurence Ris
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040823
Abstract: Current thinking about LTP triggered in the area CA1 of hippocampal slices is ruled by two “dogmas”: (1) A single train of high-frequency stimulation is sufficient to trigger short-lasting LTP (1 – 3 h), whereas multiple trains are required to induce long-lasting LTP (L-LTP, more than 4 h). (2) The development of the late phase of L-LTP requires the synthesis of new proteins. In this study, we found that a single high-frequency train could trigger an LTP lasting more than 8 h that was not affected by either anisomycin or cycloheximide (two inhibitors of protein synthesis). We ascertained that the induction of this L-LTP made use of the same mechanisms as those usually reported to be involved in LTP induction: it was dependent on NMDA receptors and on the activation of two “core” kinases, CaMKII and PI3K. These findings call into question the two “dogmas” about LTP.
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