Loss of long-term depression in the insular cortex after tail amputation in adult mice
© Liu and Zhuo; licensee BioMed Central Ltd. 2014
Received: 1 November 2013
Accepted: 30 December 2013
Published: 8 January 2014
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.
Insular cortex (IC) is an integrating forebrain structure involved in several sensory and cognitive functions, such as interoceptive awareness, taste memory, and pain perception [1–3]. In particular, human brain imaging studies have demonstrated the activation of IC in a broad range of pain conditions [4–6]. Moreover, electrical stimulation of IC directly elicits painful sensations in human subjects [7–9]. The involvement of IC in chronic pain has also been confirmed by animal experiments, showing the presence of nociceptive neurons [10, 11] and pain-evoked biochemical changes [12, 13] in this area. Genetic [14, 15] or pharmacological [16–19] manipulation of the IC could alter the pain sensitivity. Importantly, long-term potentiation (LTP) has been revealed in the IC by both in vivo [20, 21] and in vitro [22, 23] electrophysiological recordings. Furthermore, neuropathic pain experience could occlude the electrical induction of insular LTP in adult mice , suggesting that chronic pain may share common mechanisms with insular synaptic plasticity .
Phantom pain refers to the feeling of pain in a body part that has been amputated [25–27]. Mechanistically, limb amputation has been shown to cause dramatic cortical reorganization in humans and primates [28–31], the amount of which correlates well with the extent of phantom pain in some reports [32–34]. We previously demonstrated that digit amputation in rats or tail amputation in mice triggered long-lasting plastic alterations in the anterior cingulate cortex (ACC), including an enhancement of excitatory synaptic responses in vivo [35, 36], loss of long-term depression (LTD) in vitro [37, 38] and activation of activity-dependent immediate early genes [37, 39]. In addition to ACC, human imaging studies also revealed a correlation between the IC activation and phantom pain [25, 40, 41]. Thus, it is important to investigate the possible changes in synaptic plasticity in the IC after amputation.
Summary of previous studies on injury-evoked changes in the induction of LTD
Field potential recording
LFS (1 Hz, 15 min)
No effect on LTD induction
LFS (5 Hz, 3 min)
Partial sciatic nerve ligation
Field potential recording
LFS (1 Hz, 15 min)
No effect on LTD induction
Field potential recording
ACC and parietal cortex
LFS (1 Hz, 15 min)
Lost LTD in the ACC but not parietal cortex
LFS (5 Hz, 3 min)
64-channel field potential recording
LFS (1 Hz, 15 min)
Rescue of lost LTD by mGluR1 activation
Bone cancer pain
Whole-cell patch-clamp recording
Impaired LTD accompanied by reduced NMDA receptor expression
64-channel field potential recording
LFS (1 Hz, 15 min)
Impaired electrical LTD
The present study
Intact chemical LTD
Loss of LFS-evoked LTD in the IC after tail amputation
Furthermore, we analyzed the induction ratio of insular LTD, defined as the percentage of LTD-showing channels among all activated channels. This ratio was greatly decreased in the tail-amputated slices (superficial layer: 15.5 ± 2.9%, P < 0.001, Student’s t-test; deep layer: 17.7 ± 4.8%, P < 0.001, Student’s t-test) compared to the sham control (superficial layer: 59.4 ± 6.0%; deep layer: 48.9 ± 4.7%, Figure 2B). Similar results were obtained with stimulation at another frequency (5 Hz, 3 min; data not shown). These findings suggest that tail amputation results in an inability of insular synapses to undergo LTD, regardless of the specific layer.
Lack of the effect of amputation on DHPG-induced insular LTD
Enhanced synaptic transmission in the IC after tail amputation
Pharmacological rescue of LFS-evoked insular LTD after tail amputation
Protein kinase C, but not CaMKII or PKA, is involved in the rescue of insular LTD
Besides PKC, CaMKII and PKA have also been shown to mediate certain forms of metaplasticity [66–68]. Therefore, we also evaluated the role of these two kinases in DHPG-rescued insular LTD in the tail-amputated mice. As shown in Figure 6C-E, neither KN62 (5 μM, a CaMKII inhibitor) nor KT5720 (1 μM, a PKA inhibitor) could block the induction of LTD in the superficial layer of the IC (KN62: 65.0 ± 3.5% of baseline, n = 6 slices/5 mice, P = 0.595, One-Way ANOVA followed by Fisher’s LSD test; KT5720: 72.6 ± 3.9% of baseline, n = 7 slices/5 mice, P = 0.558, One-Way ANOVA followed by Fisher’s LSD test). Similar results were obtained in the deep layer (KN62: 72.8 ± 2.6% of baseline, n = 6 slices/5 mice, P = 0.382, One-Way ANOVA followed by Fisher’s LSD test; KT5720: 81.9 ± 1.9% of baseline, n = 7 slices/5 mice, P = 0.544, One-Way ANOVA followed by Fisher’s LSD test, Figure 7C-E). These observations are consistent with our previous results in the ACC , suggesting that PKC, but not CaMKII or PKA, acts as a major mediator in mGluR-evoked metaplasticity in the IC in tail-amputated animals.
There is considerable evidence indicating the critical role of the IC in pain perception and memory storage [2, 3, 16–18]. However, few studies have been conducted at the cellular level to address the synaptic basis of IC-mediated higher brain functions. 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]. Since cortical plasticity has been proposed to be an endpoint measurement and working mechanism of chronic pain [24, 69], it would be interesting to address the metaplastic effects of chronic pain experience in vivo on the induction of insular LTP and LTD in vitro. We recently report that nerve injury-induced neuropathic pain could fully occlude the subsequent induction of LTP in the IC . In the present study, using a 64-channel multi-electrode array system, we further evaluated the effect of abnormal pain processing on insular LTD. We found that a two-week experience of amputation-induced peripheral injury resulted in a selective impairment of insular LTD induction by the LFS protocol, but without any effect on DHPG-induced LTD. Priming the IC slices with pharmacological activation of group I mGluRs rescued the LFS-induced LTD after amputation, which involves the activation of PKC, but not PKA or CaMKII.
Loss of LTD in the IC after amputation
One of the central findings in this study is the loss of LFS-evoked LTD in tail-amputated IC slices. We selected two weeks after amputation as the time point for taking the IC slices for multi-channel recordings, mainly based on our previous publications showing the occurrence of marked plastic changes in the ACC at this time. Specifically, we found that peripheral amputation abolished LTD and enhanced extracellular signal-regulated kinase activation in the rodent ACC at two weeks [37–39]. Nevertheless, amputation-caused plastic changes in the brain might be time-dependent. For example, digit amputation can abolish ACC LTD and enhance hippocampal LTP at 45 min but failed to elicit any significant change in the hippocampus at 20 min or earlier [37, 45]. Thus, future studies are clearly needed to investigate if tail amputation-induced loss of insular LTD is time dependent, and if so, when the metaplastic alterations are initiated and how long they can last.
The detailed mechanisms underlying this LTD abolishment are not well understood. However, our previous work revealed a similar deficit of LTD induction in the ACC from adult rats or mice subjecting to digit or tail amputation, respectively [37, 38]. In addition, tissue amputation produced a rapid and prolonged enhancement of sensory responses to noxious stimulation, dramatic membrane depolarization, as well as large-scale expression of several immediate early genes and signaling molecules in the ACC [35, 37, 39, 70], for review, see . These observations allow us to speculate that enhanced postsynaptic excitability might also occur in the IC after tail amputation, which leads to the failure of LTD induction. Supporting this assertion, we found a leftward shift of input–output curves of fEPSPs in tail-amputated slices as compared to the control group. Furthermore, our recent work demonstrates that induction of insular LTD by LFS involves activation of the NMDA receptor and mGluR5 . Since DHPG-induced LTD is not affected by amputation (see below), an alternative explanation for the loss of LFS-evoked LTD might be due to the changes in the expression and/ or function of NMDA receptor in the IC caused by tail amputation. Injury-induced deficits in signaling cascades at the downstream of the NMDA receptor activation may also contribute to the loss of insular LTD. 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].
DHPG-induced LTD is not affected by tail amputation
One unexpected finding of this study is that tail amputation did not affect the induction of DHPG-LTD in superficial and deep layers of the IC. These results stand in contrast with those obtained from the adult mice ACC slices, where both electrically-induced LTD and chemically-induced LTD were significantly impaired by tail amputation . The exact reasons for these discrepancies are not clear but might be due to the differences in the mGluR-targeting drugs used (DHPG vs. DHPG + MPEP) and the forebrain regions analyzed (IC vs. ACC). The conflicting observations between LFS-and DHPG-induced insular LTD could arise from their differences in the vulnerability to amputation-elicited plastic changes in the IC area. This discrepancy is also in accordance with our recent publication, demonstrating that DHPG-LTD and LFS-induced LTD represent two distinct forms of LTD co-existing in the insular synapses and do not occlude each other .
It is noteworthy that region-related differences might exist when considering the effects of tissue amputation on synaptic plasticity in the pain-related brain regions (summarized in Table 1). Specifically, although either tail or digit amputation triggered a complete loss of LTD in the ACC [37, 38] or the IC (the present study), almost the same manipulation has no effect on LTD induction in the hippocampus or parietal cortex [37, 45]. Also, partial ligation of the sciatic nerve, a well-established animal model of neuropathic pain, does not affect the induction of LFS-evoked LTD in the hippocampus . These findings indicate that both ACC and IC play important roles in amputation-related cortical plasticity, and such changes are relatively selective for pain-related areas. It is unlikely due to the general stress or other non-selective factors caused by amputation. 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].
mGluR-dependent rescue of insular LTD after tail amputation
It is now well-known that mGluRs activation is not only directly involved in the induction of LTP or LTD, but is also engaged in a process called metaplasticity, by which prior neuronal activity or mGluRs activation can affect the subsequent ability to exhibit synaptic plasticity [for reviews, see [61, 71–73]. Nevertheless, the current literature mainly indicates the metaplastic role of mGluRs in facilitation of hippocampal LTP induction, with less emphasis placed upon their effect on LTD in cortical areas [59, 60, 74, 75]. 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 . Our recent work in the ACC revealed a facilitatory role of prior mGluR1 activation on cingulate LTD induction in the tail-amputated mice . Consistently, the present study demonstrated a similar rescue of amputation-impaired insular LTD by priming treatment with DHPG (20 μM, 20 min). This is the first demonstration of the metaplasticity phenomenon in the adult mouse IC. More importantly, these observations highlight the potential of developing mGluR agonists as a novel therapeutic strategy against phantom pain (see below).
Intracellular protein kinases mediating the pharmacological rescue
In the present study, we also examined the mechanisms of group I mGluR-mediated metaplastic rescue of insular LTD. Previously, evidence has been obtained to support the role of PKC in various types of metaplasticity, including NMDA receptor- or prior synaptic activity-induced subsequent LTP inhibition and LTD facilitation [63, 78], mGluRs-mediated LTP enhancement [64, 74, 79] and inhibition of chemically- or electrically-induced LTD initiation [65, 80]. Here, we have added the new findings that PKC activation is also an important contributing factor governing group I mGluR-mediated metaplastic rescue of amputation-impaired insular LTD. By contrast, we did not find any participation of PKA or CaMKII in the process, although there are some previous reports indicating their involvement in the regulation of metaplasticity [66–68]. Consistently, our previous work found that amputation-induced loss of LTD in the ACC was rescued by mGluR1-related PKC-dependent mechanisms , suggesting the important roles of PKC in mGluR-evoked metaplasticity in both ACC and IC. It is well known that group I mGluR activation can lead to intracellular calcium rise and subsequent PKC activation [81, 82]. Also, the function of the NMDA receptor can be regulated through PKC-mediated signaling pathways [74, 83, 84]. Recently, we reported that the NMDA receptor is involved in the induction of LFS-evoked LTD in the IC . It is thus reasonable to speculate that bath application of DHPG might result in significant PKC activation, which then contributes to the restoration of insular LTD through possible NMDA receptor-related mechanisms in the IC slices from tail-amputated mice. Importantly, inhibition of PKC did not affect the LTD induction in naïve IC slices , implying that mechanistic differences do exist between synaptic plasticity and metaplasticity in the IC.
Phantom pain is a common form of chronic pain syndrome characterized by the feeling of pain in the missing limb following amputation or deafferentation [25–27]. Until now, the clinical treatment for phantom pain is still limited and inefficient. Maladaptive plastic changes along the neuroaxis have been proposed to be associated with the occurrence and intensity of phantom pain [25, 31, 32, 85]. Therefore, reversing these plastic changes may offer a novel way to improve the treatment of phantom pain or amputation-related brain dysfunctions. Our previous and present results reveal a loss of LFS-induced LTD in the ACC  and IC (the present study) following tail amputation in the adult mice, providing an alternative mechanism by which peripheral injury elicits long-lasting alterations in synaptic transmission and function in the central nervous system [37, 42, 47], also see Table 1]. Furthermore, we demonstrate that priming treatment with DHPG application could rescue the lost LTD in both ACC and IC after amputation, indicating that drugs acting at group I mGluRs might hold promise for the rational treatment of phantom pain by reversing amputation-evoked synaptic dysfunctions in the neocortex. From a clinical perspective, the multi-synaptic model established in the present study might be useful for further elucidating synaptic mechanisms of phantom pain in the brain, as well as screening and developing potential new drugs for treating this intractable disease in the human amputees.
Experiments were performed with adult (7-10 week old) male C57/BL6 mice purchased from Charles River (Quebec, Canada). All animals were fed in groups of three per cage under standard laboratory conditions (12 h light/12 h dark, temperature 22-26°C, air humidity 55-60%) with ad libitum water and mice chow. The experimental procedures were approved by the Institutional Animal Care and Use Committee of The University of Toronto. All animals were maintained and cared for in compliance with the guidelines set forth by the International Association for the Study of Pain . The number of animals used and their suffering were greatly minimized.
The drugs used in this study include: DHPG, chelerythrine, KT5720 and KN62. Among them, chelerythrine and DHPG were dissolved in distilled water, while KT5720 and KN62 were prepared in dimethyl sulfoxide (DMSO) as stock solutions for frozen aliquots at -20°C. All these drugs were diluted from the stock solutions to the final desired concentration in the artificial cerebrospinal fluid (ACSF) before immediate use. The diluted DMSO in ACSF had no effect on baseline synaptic transmission and plasticity. Chelerythrine, KT5720 and KN62 were purchased from Tocris Cookson (Bristol, UK) and DHPG was obtained from Abcam Biochemicals (Cambridge, UK). The doses for each compound were chosen based on our preliminary experiments and on relevant information from previous papers [38, 44, 77]. For the pharmacological rescue of insular LTD, DHPG (20 μM) with or without the drugs was bath applied for 20 min and then washed out for 30 min prior to LTD induction.
The major procedures for tail amputation are in accordance with those described previously [38, 45, 87]. After anesthesia with gaseous isoflurane, the mouse was gently put in a box where a 2.5 cm length of the tail tip was removed using surgical scissors. A drop of Krazy Glue was used to stop bleeding. The mice typically recovered from anesthesia within 3-5 min. Amputated animals did not exhibit any neurological deficits or abnormal behaviors when returned to the home cage. For the sham control group, mice were anesthetized for the same period of time without any surgery. Procedure was executed with caution to minimize handling-induced stress in the mice. In the present study, we performed electrophysiological recordings at 2 weeks after tail amputation (Figure 1A), on the basis of our previous reports showing an evident plastic change in the ACC at this time point [37–39].
Insular slice preparation
The general procedures for making IC slices are similar to those described previously [18, 23, 44, 48]. Briefly, mice were anesthetized with a brief exposure to gaseous isoflurane and decapitated. The entire brain was rapidly removed and immersed into a cold bath of oxygenated (95% O2 and 5% CO2) ACSF containing (in mM): NaCl 124, KCl 2.5, NaH2PO4 1.0, MgSO4 1, CaCl2 2, NaHCO3 25 and glucose 10, pH 7.35-7.45. After cooling for 1-2 min, appropriate portions of the brain were then trimmed and the remaining brain block was glued onto the ice-cold stage of a vibrating tissue slicer (Leika, VT1000S). Following this, three coronal IC slices (300 μm) were obtained at the level of corpus callosum connection and transferred to an incubation chamber continuously perfused with oxygenated ACSF at 26°C. Slices were allowed to recover for at least 2 h before any electrophysiological recording was started.
Multi-channel field potential recordings
A commercial 64-channel multi-electrode array system (MED64, Panasonic Alpha-Med Sciences, Japan) was used for extracellular field potential recordings in this study. Procedures for preparation of the MED64 probe and multi-channel field potential recordings were similar to those described previously [23, 38, 43, 44]. The device had an array of 64 planar microelectrodes, each 50 × 50 μm in size, arranged in an 8 × 8 pattern (inter-electrode distance: 150 μm). Before use, the surface of the MED64 probe was treated with 0.1% polyethyleneimine (Sigma, St. Louis, MO, USA) in 25 mM borate buffer (pH 8.4) overnight at room temperature. After incubation, one slice was positioned on the MED64 probe in such a way that the IC area was entirely covered by the recording dish mounted on the stage of an inverted microscope (CKX41, Olympus). The relative location of the IC slice with the probe followed the anatomical atlas , also see Figure 1B]. Once the slice was settled, a fine mesh anchor (Warner Instruments, Harvard) was carefully disposed to ensure slice stabilization during recording. The slice was continuously perfused with oxygenated, fresh ACSF at the rate of 2-3 ml/min with the aid of a peristaltic pump (Minipuls 3, Gilson) throughout the entire experimental period.
After a 15-20 min recovery of the slice, one of the 64 available planar microelectrodes was selected from the 64-switch box for stimulation by visual observation through a charge-coupled device camera (DP70, Olympus) connected to the inverted microscope. For test stimulation, monopolar, biphasic constant current pulses (0.2 ms in duration) generated by the data acquisition software (Mobius, Panasonic Alpha-Med Sciences) were applied to the deep layer (layer V-VI) of the IC slice at 0.008 Hz (red dot in Figure 1B). The fEPSPs evoked at both the deep layer and the superficial layer (layer I-III) of the IC slice were amplified by a 64-channel amplifier, displayed on the monitor screen and stored on the hard disk of a microcomputer for offline analysis. After selecting the best stimulation site and stabilizing the baseline synaptic responses, an input–output curve was first determined for each group using the measurements of fEPSP slope or the number of activated channels (output) in response to a series of ascending stimulation intensities from 6 μA to 24 μA by every 2 μA step (input). For the LTD induction, the intensity of the test stimulus was adjusted to elicit 40-60% of the maximum according to the input–output curves. Stable baseline responses were then monitored for at least 20 min before delivering a classical LFS protocol (1 Hz, 900 pulses, with the same intensity as baseline recording) to induce NMDA receptor-dependent LTD. In another set of experiments, DHPG (100 μM, 20 min) was bath applied to induce another form of LTD . After LFS or DHPG application, the test stimulus was repeatedly delivered once every 2 min for 1 h or 50 min to monitor the time course of insular LTD.
All multi-channel electrophysiological data were analyzed offline by the MED64 Mobius software. For quantification of the input–output relationship, the slope of fEPSP was measured and expressed as the percentage of 8 μA value according to different layers (superficial layer and deep layer). It is notable that data from the stimulation intensity of 6 μA were not included in the slope analysis due to the much fewer fEPSP evoked at this low intensity. The number of activated channels evoked at different stimulation intensities was also counted in a blind manner. For quantification of the LTD data, the initial slope of fEPSPs was measured by taking the rising phase between 10% and 90% of the peak response, normalized and presented separately in both superficial and deep layers as a percentage change from the baseline level. The degree of LTD in each experiment was shown as the value obtained at 50 min or 60 min after DHPG or LFS treatment, respectively. For evaluation of the drug effects on rescued LTD, the averaged value of the last 10 min of the recording was compared statistically. Furthermore, the number of activated channels (over 20% of baseline, i.e. the amplitude goes over -20 μV) vs. the LTD-showing (depressed by at least 15% of baseline) channels was counted and expressed as the induction ratio of LTD (number of LTD-occurring channels /number of all activated channels × 100%). All data are shown as mean ± S.E.M. When necessary, the statistical significance was assessed by two-tailed Student’s t test and one-way ANOVA (followed by post doc Fisher’s LSD test) using the Sigma Plot software. P < 0.05 was assumed as statistically significant.
Anterior cingulate cortex
Artificial cerebrospinal fluid
Calcium/calmodulin-dependent protein kinase II
Field excitatory postsynaptic potential
64-channel multi-electrode dish
Metabotropic glutamate receptor
Protein kinase A
Protein kinase C.
This work was supported by Canadian Institutes of Health Research (CIHR) operating grant, Canada Research Chair (CRC), and NSERC (Natural Sciences and Engineering Research Council of Canada) discovery grant 402555 to MZ.
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