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Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex.

Toyoda H, Zhao MG, Ulzhöfer B, Wu LJ, Xu H, Seeburg PH, Sprengel R, Kuner R, Zhuo M - Mol Pain (2009)

Bottom Line: Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits.However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated.Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Ontario, Canada. hiroki.toyoda@utoronto.ca

ABSTRACT
Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Furthermore, GluA1 knockout mice showed decreased extracellular signal-regulated kinase (ERK) phosphorylation in the ACC in inflammatory pain models in vivo. Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.

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Reduced AMPA receptor-mediated EPSCs in GluA2-/- mice. (A) Input-output relationships for AMPA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA2-/- (n = 6) mice (left). * P < 0.05 compared with WT mice. Traces showing averages of five AMPA receptor-mediated EPSCs with input stimulation at 9 V (right). (B) Paired-pulse facilitaion (PPF) did not differ in WTCD1 (n = 7) and GluA2-/- (n = 13) mice (left). Sample traces of PPF recorded from WTCD1 and GluA2-/- mice at the 50 ms interval (right). (C) Traces of mEPSCs recorded from WTCD1 and GluA2-/- mice (Top). Summary results showing the frequency and the amplitude of mEPSCs in ACC neurons from WT (n = 8) and GluA2-/- (n = 9) mice (Bottom, left). Cumulative probability plot showing the distribution of the inter-event interval and the frequency in WTCD1 (n = 8) and GluA1-/- mice (n = 9) (Bottom, right). (D) Input-output relationships for NMDA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA1-/- mice (n = 6) (left). Traces showing averages of five NMDA receptor-mediated EPSCs with input stimulation at 12 V (right).
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Figure 5: Reduced AMPA receptor-mediated EPSCs in GluA2-/- mice. (A) Input-output relationships for AMPA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA2-/- (n = 6) mice (left). * P < 0.05 compared with WT mice. Traces showing averages of five AMPA receptor-mediated EPSCs with input stimulation at 9 V (right). (B) Paired-pulse facilitaion (PPF) did not differ in WTCD1 (n = 7) and GluA2-/- (n = 13) mice (left). Sample traces of PPF recorded from WTCD1 and GluA2-/- mice at the 50 ms interval (right). (C) Traces of mEPSCs recorded from WTCD1 and GluA2-/- mice (Top). Summary results showing the frequency and the amplitude of mEPSCs in ACC neurons from WT (n = 8) and GluA2-/- (n = 9) mice (Bottom, left). Cumulative probability plot showing the distribution of the inter-event interval and the frequency in WTCD1 (n = 8) and GluA1-/- mice (n = 9) (Bottom, right). (D) Input-output relationships for NMDA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA1-/- mice (n = 6) (left). Traces showing averages of five NMDA receptor-mediated EPSCs with input stimulation at 12 V (right).

Mentions: We also examined AMPA receptor-mediated EPSCs in GluA2-/- mice in the presence of 50 μM AP-5. As with GluA1-/- mice, GluA2-/- mice (n = 6) also showed reduced AMPA receptor-mediated EPSCs at all stimulus intensities compared with WTCD1 mice (n = 6) (Fig. 5A, left). The rise time and decay time in AMPA receptor-mediated EPSCs with input stimulation at 9 V showed no significant difference in GluA2-/- (rise time, 3.1 ± 0.1 ms; decay time, 17.6 ± 1.3 ms, n = 6) mice in comparison with WTCD1 mice (rise time, 3.1 ± 0.1 ms; decay time, 17.6 ± 1.3 ms, n = 6) (Fig. 5A, right).


Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex.

Toyoda H, Zhao MG, Ulzhöfer B, Wu LJ, Xu H, Seeburg PH, Sprengel R, Kuner R, Zhuo M - Mol Pain (2009)

Reduced AMPA receptor-mediated EPSCs in GluA2-/- mice. (A) Input-output relationships for AMPA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA2-/- (n = 6) mice (left). * P < 0.05 compared with WT mice. Traces showing averages of five AMPA receptor-mediated EPSCs with input stimulation at 9 V (right). (B) Paired-pulse facilitaion (PPF) did not differ in WTCD1 (n = 7) and GluA2-/- (n = 13) mice (left). Sample traces of PPF recorded from WTCD1 and GluA2-/- mice at the 50 ms interval (right). (C) Traces of mEPSCs recorded from WTCD1 and GluA2-/- mice (Top). Summary results showing the frequency and the amplitude of mEPSCs in ACC neurons from WT (n = 8) and GluA2-/- (n = 9) mice (Bottom, left). Cumulative probability plot showing the distribution of the inter-event interval and the frequency in WTCD1 (n = 8) and GluA1-/- mice (n = 9) (Bottom, right). (D) Input-output relationships for NMDA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA1-/- mice (n = 6) (left). Traces showing averages of five NMDA receptor-mediated EPSCs with input stimulation at 12 V (right).
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Related In: Results  -  Collection

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Figure 5: Reduced AMPA receptor-mediated EPSCs in GluA2-/- mice. (A) Input-output relationships for AMPA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA2-/- (n = 6) mice (left). * P < 0.05 compared with WT mice. Traces showing averages of five AMPA receptor-mediated EPSCs with input stimulation at 9 V (right). (B) Paired-pulse facilitaion (PPF) did not differ in WTCD1 (n = 7) and GluA2-/- (n = 13) mice (left). Sample traces of PPF recorded from WTCD1 and GluA2-/- mice at the 50 ms interval (right). (C) Traces of mEPSCs recorded from WTCD1 and GluA2-/- mice (Top). Summary results showing the frequency and the amplitude of mEPSCs in ACC neurons from WT (n = 8) and GluA2-/- (n = 9) mice (Bottom, left). Cumulative probability plot showing the distribution of the inter-event interval and the frequency in WTCD1 (n = 8) and GluA1-/- mice (n = 9) (Bottom, right). (D) Input-output relationships for NMDA receptor-mediated EPSCs in WTCD1 (n = 6) and GluA1-/- mice (n = 6) (left). Traces showing averages of five NMDA receptor-mediated EPSCs with input stimulation at 12 V (right).
Mentions: We also examined AMPA receptor-mediated EPSCs in GluA2-/- mice in the presence of 50 μM AP-5. As with GluA1-/- mice, GluA2-/- mice (n = 6) also showed reduced AMPA receptor-mediated EPSCs at all stimulus intensities compared with WTCD1 mice (n = 6) (Fig. 5A, left). The rise time and decay time in AMPA receptor-mediated EPSCs with input stimulation at 9 V showed no significant difference in GluA2-/- (rise time, 3.1 ± 0.1 ms; decay time, 17.6 ± 1.3 ms, n = 6) mice in comparison with WTCD1 mice (rise time, 3.1 ± 0.1 ms; decay time, 17.6 ± 1.3 ms, n = 6) (Fig. 5A, right).

Bottom Line: Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits.However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated.Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Ontario, Canada. hiroki.toyoda@utoronto.ca

ABSTRACT
Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Furthermore, GluA1 knockout mice showed decreased extracellular signal-regulated kinase (ERK) phosphorylation in the ACC in inflammatory pain models in vivo. Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.

Show MeSH
Related in: MedlinePlus