Loss of long-term depression in the insular cortex after tail amputation in adult mice
TL;DR: It is found that tail amputation in adult mice produced a selective loss of low frequency stimulation-induced LTD in the IC, without affecting (RS)-3,5-dihydroxyphenylglycine (DHPG)-evoked LTD, and it is suggested that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.
Abstract: The insular cortex (IC) is an important forebrain structure involved in pain perception and taste memory formation. Using a 64-channel multi-electrode array system, we recently identified and characterized two major forms of synaptic plasticity in the adult mouse IC: long-term potentiation (LTP) and long-term depression (LTD). In this study, we investigate injury-related metaplastic changes in insular synaptic plasticity after distal tail amputation. We found that tail amputation in adult mice produced a selective loss of low frequency stimulation-induced LTD in the IC, without affecting (RS)-3,5-dihydroxyphenylglycine (DHPG)-evoked LTD. The impaired insular LTD could be pharmacologically rescued by priming the IC slices with a lower dose of DHPG application, a form of metaplasticity which involves activation of protein kinase C but not protein kinase A or calcium/calmodulin-dependent protein kinase II. These findings provide important insights into the synaptic mechanisms of cortical changes after peripheral amputation and suggest that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.
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TL;DR: The results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.
Abstract: Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.
76 citations
Cites background from "Loss of long-term depression in the..."
...Peripheral nerve injury or tail amputation produces long-term upregulation or activation of the synaptic NMDARs (Zhuo, 1998; Qiu et al., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....
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..., 2013) or loss of long-term depression in the insular cortex (Liu and Zhuo, 2014)....
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TL;DR: LTP of glutamatergic transmission in pain related cortical areas serves as a key mechanism for chronic pain.
65 citations
TL;DR: There is strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission and basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain are provided.
Abstract: Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain.
41 citations
Cites background from "Loss of long-term depression in the..."
...in sensory and emotion-related cortical areas such as the insular cortex (IC) and anterior cingulate cortex (ACC), both E-LTP and L-LTP have been recently reported in adult mice [11-14]....
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TL;DR: It is found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region.
Abstract: The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.
39 citations
TL;DR: Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.
Abstract: Commercial pigs are frequently exposed to tail mutilations in the form of preventive husbandry procedures (tail docking) or as a result of abnormal behaviour (tail biting). Although tissue and nerve injuries are well-described causes of pain hypersensitivity in humans and in rodent animal models, there is no information on the changes in local pain sensitivity induced by tail injuries in pigs. To determine the temporal profile of sensitisation, pigs were exposed to surgical tail resections and mechanical nociceptive thresholds (MNT) were measured in the acute (one week post-operatively) and in the long-term (either eight or sixteen weeks post-surgery) phase of recovery. The influence of the degree of amputation on MNTs was also evaluated by comparing three different tail-resection treatments (intact, 'short tail', 'long tail'). A significant reduction in MNTs one week following surgery suggests the occurrence of acute sensitisation. Long-term hypersensitivity was also observed in tail-resected pigs at either two or four months following surgery. Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.
35 citations
References
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TL;DR: The results indicate that tumor‐induced injury or remodeling of primary afferent sensory nerve fibers that innervate the tumor‐bearing bone may cause a persistent decrease in NMDA receptor expression in rACC neurons, resulting in a loss of LTD induction, thereby leading to long‐term alterations of rACC activity and creating exaggerated pain behaviors.
Abstract: The anterior cingulate cortex (ACC) has been shown to play an important role in pain-related perception and chronic pain. However, little is known about the molecular mechanisms involved. To address this issue, we analyzed excitatory synaptic transmission and long-term synaptic plasticity in layer II/III pyramidal neurons within the rostral ACC (rACC) from mice with bone cancer pain induced by intra-tibia implantation of osteolytic fibrosarcoma cells. Ex vivo whole-cell patch-clamp recordings from rACC neurons showed no significant alterations in presynaptic glutamate release probability and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses in mice with bone cancer pain. However, mechanical allodynia occurred in conjunction with decreased N-methyl-d-aspartate (NMDA)/AMPA ratio of synaptic currents elicited in bilateral rACC neurons. In addition, the induction of NMDA receptor-dependent long-term depression (LTD) at rACC synapses was impaired in rACC neurons of tumor-bearing mice. Western blot analysis revealed a significant decrease in the levels of NR1, NR2A, and NR2B subunits of NMDA receptors in the rACC under bone cancer pain condition. No significant changes in overall mRNA levels for any of the NMDA receptor subunits or calpain activity were observed in the rACC of tumor-bearing mice. These results indicate that tumor-induced injury or remodeling of primary afferent sensory nerve fibers that innervate the tumor-bearing bone may cause a persistent decrease in NMDA receptor expression in rACC neurons, resulting in a loss of LTD induction, thereby leading to long-term alterations of rACC activity and creating exaggerated pain behaviors.
25 citations
TL;DR: Using whole cell patch-clamp recordings, it is shown that KA receptors contribute to fast synaptic transmission in neurons in all layers of the insular cortex (IC) and may provide the synaptic basis for the physiology and pathology of KA receptor in the IC-related functions.
Abstract: Kainate (KA) receptors are expressed widely in the central nervous system and regulate both excitatory and inhibitory synaptic transmission. KA receptors play important roles in fear memory, anxiet...
21 citations
"Loss of long-term depression in the..." refers background or result in this paper
...The general procedures for making IC slices are similar to those described previously [18,23,44,48]....
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...Our recent work demonstrates that fast excitatory synaptic transmission in the IC is mainly mediated by postsynaptic AMPA/kainate receptors and that both LTP and LTD could be induced reliably but with different receptor mechanisms [23,44,48]....
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...Neurons in different layers of the IC are considered to have different afferent and efferent connections with other areas of the brain, and thus may mediate distinct functions [48-50]....
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TL;DR: The ability of priming activation of metabotropic glutamate receptors to regulate long-term depression was studied in area CA1 of hippocampal slices taken from young adult male rats, finding that activation of Group II mGluRs is also known to inhibit LTP.
14 citations
"Loss of long-term depression in the..." refers background or methods in this paper
...The doses for each compound were chosen based on our preliminary experiments and on relevant information from previous papers [38,44,77]....
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...There are only a few reports showing that priming stimulation of group II mGluRs inhibits or facilitates the subsequent induction of LTD in CA1 or dentate gyrus, respectively [76,77], while prior activation of group I mGluRs has no effect [77]....
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TL;DR: The original article to which this Erratum refers was published in The Journal of Comparative Neurology (2004) 468: 311–465.
Abstract: The original article to which this Erratum refers was published in The Journal of Comparative Neurology (2004) 468: 311–465.
13 citations
TL;DR: Recent progresses of the cortical plasticity in the anterior cingulate cortex (ACC), a critical cortical area for pain sensation, are reviewed and how they are related to abnormal sensory sensations such as phantom pain are explored.
Abstract: People experience the feeling of the missing body part long after it has been removed after amputation are known as phantom limb sensations. These sensations can be painful, sometimes becoming chronic and lasting for several years (or called phantom pain). Medical treatment for these individuals is limited. Recent neurobiological investigations of brain plasticity after amputation have revealed new insights into the changes in the brain that may cause phantom limb sensations and phantom pain. In this article, I review recent progresses of the cortical plasticity in the anterior cingulate cortex (ACC), a critical cortical area for pain sensation, and explore how they are related to abnormal sensory sensations such as phantom pain. An understanding of these alterations may guide future research into medical treatment for these disorders.
8 citations
"Loss of long-term depression in the..." refers background in this paper
...Regardless of the mechanisms, loss of the ability to undergo LTD in the IC might be an essential synaptic mechanism accounting for the maladaptive central plasticity occurring after amputation [25,26,42]....
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...Targeting these alterations in synaptic plasticity in the brain might provide an alternative approach for the treatment of chronic pain including the phantom pain [24,25,42,69]....
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