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Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury.

Chen T, Koga K, Descalzi G, Qiu S, Wang J, Zhang LS, Zhang ZJ, He XB, Qin X, Xu FQ, Hu J, Wei F, Huganir RL, Li YQ, Zhuo M - Mol Pain (2014)

Bottom Line: After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced.Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information.Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China. deptanat@fmmu.edu.cn.

ABSTRACT
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.

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GluA1/3 mediated the potentiation of the AMPAR mediated basal synaptic transmission in ACC-spinal cord projecting neurons. A, Samples and the averaged results showing that NASPM inhibited the AMPAR EPSCs in mice with nerve injury but not in mice with sham surgery. B, Samples and averaged results showing that NASPM only inhibited the AMPAR EPSCs in ACC-SC projecting neurons in mice with nerve injury but not in mice with sham surgery. C, NASPM did not inhibit the AMPAR EPSCs in ACC-VS projecting neurons in mice either with or without nerve injury. D, Plotted figure shows the summarized effect of NASPM on unlabeled or retrograded labeled projecting neurons. E-G, NASPM can only inhibit the AMPAR EPSCs of ACC-SC projecting neurons in s831A mice with nerve injury, but not in s845A mice with nerve injury, as well as s831A and s845A mice with sham surgery. *,p < 0.05; **,p < 0.01; ***,p < 0.001.
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Figure 7: GluA1/3 mediated the potentiation of the AMPAR mediated basal synaptic transmission in ACC-spinal cord projecting neurons. A, Samples and the averaged results showing that NASPM inhibited the AMPAR EPSCs in mice with nerve injury but not in mice with sham surgery. B, Samples and averaged results showing that NASPM only inhibited the AMPAR EPSCs in ACC-SC projecting neurons in mice with nerve injury but not in mice with sham surgery. C, NASPM did not inhibit the AMPAR EPSCs in ACC-VS projecting neurons in mice either with or without nerve injury. D, Plotted figure shows the summarized effect of NASPM on unlabeled or retrograded labeled projecting neurons. E-G, NASPM can only inhibit the AMPAR EPSCs of ACC-SC projecting neurons in s831A mice with nerve injury, but not in s845A mice with nerve injury, as well as s831A and s845A mice with sham surgery. *,p < 0.05; **,p < 0.01; ***,p < 0.001.

Mentions: AMPAR is heterotetramer of four homologous subunits (GluA1 to GluA4) that combine in different stoichiometries to form different subunits [43]. In normal conditions, most of the AMPAR contain the GluA2 subunit. During synaptic plastic changes, GluA2 can be replaced by GluA1/3 subunit [44,45], which is Ca2+ permeable AMPAR (CP-AMPAR) and inwardly rectifying [46]. According to the observed inward rectification of the mean I-V curve in mice with nerve injury (Figure 5C), we expect that the potentiated AMPAR mediated responses in the ACC layer V may be sensitive to the inhibition of CP-AMPAR antagonist NASPM. We next recorded AMPAR mediated responses from ACC neurons in mice with nerve injury and found that NASPM inhibited the I-O responses (F(1, 80) = 29.163, p < 0.001, n = 9 neurons/6 mice, two way ANOVA followed with Tukey’s post hoc test). Meanwhile, NASPM didn’t inhibit the I-O responses in mice with sham surgery (F(1, 80) =0.849, p > 0.05, n = 9 neurons/6 mice, two way ANOVA) (Figure 6C). Furthermore, the AMPAR mediated eEPSCs were significantly inhibited by bath application of NASPM (50 μM) (75.3 ± 6.0% of baseline; n = 8 neurons/7 mice, paired t-test, p < 0.05). The same application of NASPM did not affect AMPAR mediated responses in ACC neurons recorded from mice with sham surgery (95.0 ± 5.2% of baseline; n = 7 neurons/6 mice, p > 0.05) (Figure 7A).


Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury.

Chen T, Koga K, Descalzi G, Qiu S, Wang J, Zhang LS, Zhang ZJ, He XB, Qin X, Xu FQ, Hu J, Wei F, Huganir RL, Li YQ, Zhuo M - Mol Pain (2014)

GluA1/3 mediated the potentiation of the AMPAR mediated basal synaptic transmission in ACC-spinal cord projecting neurons. A, Samples and the averaged results showing that NASPM inhibited the AMPAR EPSCs in mice with nerve injury but not in mice with sham surgery. B, Samples and averaged results showing that NASPM only inhibited the AMPAR EPSCs in ACC-SC projecting neurons in mice with nerve injury but not in mice with sham surgery. C, NASPM did not inhibit the AMPAR EPSCs in ACC-VS projecting neurons in mice either with or without nerve injury. D, Plotted figure shows the summarized effect of NASPM on unlabeled or retrograded labeled projecting neurons. E-G, NASPM can only inhibit the AMPAR EPSCs of ACC-SC projecting neurons in s831A mice with nerve injury, but not in s845A mice with nerve injury, as well as s831A and s845A mice with sham surgery. *,p < 0.05; **,p < 0.01; ***,p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4060852&req=5

Figure 7: GluA1/3 mediated the potentiation of the AMPAR mediated basal synaptic transmission in ACC-spinal cord projecting neurons. A, Samples and the averaged results showing that NASPM inhibited the AMPAR EPSCs in mice with nerve injury but not in mice with sham surgery. B, Samples and averaged results showing that NASPM only inhibited the AMPAR EPSCs in ACC-SC projecting neurons in mice with nerve injury but not in mice with sham surgery. C, NASPM did not inhibit the AMPAR EPSCs in ACC-VS projecting neurons in mice either with or without nerve injury. D, Plotted figure shows the summarized effect of NASPM on unlabeled or retrograded labeled projecting neurons. E-G, NASPM can only inhibit the AMPAR EPSCs of ACC-SC projecting neurons in s831A mice with nerve injury, but not in s845A mice with nerve injury, as well as s831A and s845A mice with sham surgery. *,p < 0.05; **,p < 0.01; ***,p < 0.001.
Mentions: AMPAR is heterotetramer of four homologous subunits (GluA1 to GluA4) that combine in different stoichiometries to form different subunits [43]. In normal conditions, most of the AMPAR contain the GluA2 subunit. During synaptic plastic changes, GluA2 can be replaced by GluA1/3 subunit [44,45], which is Ca2+ permeable AMPAR (CP-AMPAR) and inwardly rectifying [46]. According to the observed inward rectification of the mean I-V curve in mice with nerve injury (Figure 5C), we expect that the potentiated AMPAR mediated responses in the ACC layer V may be sensitive to the inhibition of CP-AMPAR antagonist NASPM. We next recorded AMPAR mediated responses from ACC neurons in mice with nerve injury and found that NASPM inhibited the I-O responses (F(1, 80) = 29.163, p < 0.001, n = 9 neurons/6 mice, two way ANOVA followed with Tukey’s post hoc test). Meanwhile, NASPM didn’t inhibit the I-O responses in mice with sham surgery (F(1, 80) =0.849, p > 0.05, n = 9 neurons/6 mice, two way ANOVA) (Figure 6C). Furthermore, the AMPAR mediated eEPSCs were significantly inhibited by bath application of NASPM (50 μM) (75.3 ± 6.0% of baseline; n = 8 neurons/7 mice, paired t-test, p < 0.05). The same application of NASPM did not affect AMPAR mediated responses in ACC neurons recorded from mice with sham surgery (95.0 ± 5.2% of baseline; n = 7 neurons/6 mice, p > 0.05) (Figure 7A).

Bottom Line: After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced.Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information.Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China. deptanat@fmmu.edu.cn.

ABSTRACT
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.

Show MeSH
Related in: MedlinePlus