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Rap2-JNK Removes Synaptic AMPA Receptors during Depotentiation

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1 Rap2-JNK Removes Synaptic AMPA Receptors during Depotentiation
Yinghua Zhu, Daniel Pak, Yi Qin, Stefanie G. McCormack, Myung J. Kim, Joel P. Baumgart, Vanisree Velamoor, Yves P. Auberson, Pavel Osten, Linda van Aelst, Morgan Sheng, J. Julius Zhu  Neuron  Volume 46, Issue 6, Pages (June 2005) DOI: /j.neuron Copyright © 2005 Elsevier Inc. Terms and Conditions

2 Figure 1 Expression of Rap2 in Hippocampal CA1 Cells
(A) (Left) Expression of endogenous and recombinant Rap2 proteins in hippocampal CA1 regions, whole hippocampi, and hippocampal CA1 regions expressing Rap2-GFP. (Right) Relative amounts of endogenous Rap2 in whole hippocampi (n = 11; p < 0.05) or recombinant Rap2 in hippocampal CA1 regions expressing Rap2-GFP (n = 11; p < 0.005). The relative values and standard errors were normalized to average amounts of endogenous Rap2 from hippocampal CA1 regions. (B) Two-photon images of GFP fluorescence indicate that Rap2-GFP proteins are present in the dendrites and spines of CA1 pyramidal neurons. The dendritic spines are demarcated by RFP fluorescence. (C) (Upper) Evoked AMPA-R-mediated (−60 mV) and NMDA-R-mediated (+40 mV) responses recorded from nonexpressing (Ctrl) and Rap2(ca)-GFP-expressing cells. Rap2-GFP mutants were expressed in cultured slices in normal culture media for ∼14 hr. (Lower left) AMPA responses in cells expressing Rap2(ca)-GFP (n = 14; p < 0.01) or Rap2(dd)-GFP (n = 16; p = 0.96) relative to neighboring nonexpressing control cells. (Lower right) NMDA responses in cells expressing Rap2-GFP(ca) (n = 14; p = 0.98) or Rap2(dd)-GFP (n = 16; p = 0.57) relative to neighboring nonexpressing control cells. *p < See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

3 Figure 2 NR2A-Containing NMDA-R-Stimulated Rap2 Activity Depresses Synaptic Transmission (A) Evoked AMPA-R- and NMDA-R-mediated responses recorded from nonexpressing (Ctrl) and Rap2(dn)-GFP cells or Rap2(wt)-GFP-expressing cells cultured in normal or 12 mM Mg2+ media. (B) (Left) AMPA responses in Rap2(dn)-GFP- and Rap(wt)-GFP-expressing cells cultured in normal media [n = 16, p < 0.01 for Rap2(dn)-GFP; n = 16, p < 0.05 for Rap2(wt)-GFP], media with 12 mM Mg2+ [n = 16, p = 0.92 for Rap2(dn)-GFP; n = 16, p = 0.84 for Rap2(wt)-GFP], or media with 100 μM DL-APV [n = 16, p = 0.50 for Rap2(dn)-GFP; n = 16, p = 0.94 for Rap2(wt)-GFP]. (Right) NMDA responses in Rap2(dn)-GFP- and Rap2(wt)-GFP-expressing cells cultured in normal media [n = 16, p = 0.66 for Rap2(dn)-GFP; n = 16, p = 0.76 for Rap2(wt)-GFP], media with 12 mM Mg2+ [n = 16, p = 0.54 for Rap2(dn)-GFP; n = 16, p = 0.50 for Rap2(wt)-GFP], or media with 100 μM DL-APV [n = 16, p = 0.54 for Rap2(dn)-GFP; n = 16, p = 0.41 for Rap2(wt)-GFP]. AMPA-R- and NMDA-R-mediated current amplitude and standard errors were normalized to average values from control cells. *p < 0.05 (Wilcoxon test). (C) (Left) Levels of GTP bound Rap2 in cultured hippocampal neurons at 3, 7, 15, and 30 min following treatment with 60 μM NMDA. Each lane was loaded with affinity precipitate from 200 μg total protein. (Right plot) Levels of active Rap2-GTP against time. Relative amounts of Rap2-GTP at 3 min (n = 4; paired Student’s t test; p < 0.05), 7 min (n = 4; paired Student’s t test; p < 0.01), 15 min (n = 4; paired Student’s t test; p = 0.23), and 30 min (n = 4; paired Student’s t test; p = 0.09) after NMDA application. (D) (Left) Relative levels of GTP bound Rap2 and total Rap2 in hippocampal CA1 regions prepared from slices cultured in normal media (Ctrl) or media containing 12 mM Mg2+ or 100 μM DL-APV. For each set of hippocampal CA1 cell lysate, 35 μg protein was used to purify and blot GTP bound Rap2, and 7.5 μg protein was used to directly blot total Rap2. (Right) Relative amounts of Rap2-GTP in hippocampal CA1 regions prepared from slices cultured in 12 mM Mg2+ (n = 11; p < 0.01) or 100 μM DL-APV (n = 11; p < 0.005). Relative amounts of total Rap2 in hippocampal CA1 regions prepared from slices cultured in 12 mM Mg2+ (n = 11; p = 0.33) or 100 μM DL-APV (n = 11; p = 0.89). The relative values and standard errors were normalized to average amounts of Rap2-GTP or total Rap2 from control untreated cells. (E) Evoked AMPA-R- and NMDA-R-mediated responses recorded from nonexpressing (Ctrl) and Rap2(dn)-GFP cells or Rap1(dn)-GFP-expressing cells cultured in media containing 0.4 μM Ro or 0.4 μM NVP-AAM077. (F) (Left) AMPA responses in Rap2(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 12; p < 0.05) or media with 0.4 μM NVP-AAM077 (n = 20; p = 0.75), in Rap1(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 16; p = 0.78) or media with 0.4 μM NVP-AAM077 (n = 14; p < 0.05), or in Ras(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 14; p < 0.01) or media with 0.4 μM NVP-AAM077 (n = 16; p = 0.61). (Right) NMDA responses in Rap2(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 12; p = 0.88) or media with 0.4 μM NVP-AAM077 (n = 20; p = 0.33), in Rap1(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 16; p = 0.30) or media with 0.4 μM NVP-AAM077 (n = 14; p = 0.25), or in Ras(dn)-GFP-expressing cells cultured in media with 0.4 μM Ro (n = 14; p = 0.30) or media with 0.4 μM NVP-AAM077 (n = 16; p = 0.22). AMPA-R- and NMDA-R-mediated current amplitude and standard errors were normalized to average values from control cells. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

4 Figure 3 Rap2 Signals Synaptic Depression via Activation of JNK
(A) A prominent band specifically associated with GST-Rap2(ca), indicated by the arrow, was excised and subjected to tandem mass spectrometry for protein identification, yielding 21 peptides matching to Traf2- and NCK-interacting kinase (TNIK) and 1 peptide matching to MINK2 (a TNIK-related kinase). (B) Evoked AMPA-R- and NMDA-R-mediated responses recorded from nonexpressing (Ctrl) and TNIK(dn)-GFP-expressing cells cultured in normal media or media containing 12 mM Mg2+. (C) (Left) AMPA responses in TNIK(dn)-GFP-expressing cells cultured in normal media (n = 15; p < 0.01) or media containing 12 mM Mg2+ (n = 16; p = 0.61), or TNIK(dn)-GFP and Rap2(ca)-RFP-coexpressing cells cultured in normal media (n = 16; p = 0.31). (Right) NMDA responses in Rap2(ca)-GFP-expressing cells cultured in normal media (n = 15; p = 0.82) or media containing 12 mM Mg2+ (n = 16; p = 0.61), or TNIK(dn)-GFP and Rap2(ca)-RFP-coexpressing cells cultured in normal media (n = 16; p = 0.76). AMPA-R- and NMDA-R-mediated current amplitude and standard errors were normalized to average values from control cells. (D) Evoked AMPA-R- and NMDA-R-mediated responses recorded from nonexpressing (Ctrl) and Rap2(ca)-GFP-expressing cells cultured in media containing 5 μM SP600125, 12 mM Mg2+, or FK506. (E) (Left) AMPA responses in Rap2(ca)-GFP-expressing cells cultured in media containing 5 μM SP (n = 14; p = 0.88), 5 μM SP for 12 hr followed by normal media for 4–6 hr (n = 14; p < 0.005), 2 μM SB (n = 16; p < 0.005), 25 μM PD98059 (n = 14; p < 0.005), 12 mM Mg2+ (n = 18; p < 0.005), 25 μM FK-506 (n = 14; p = 0.88), or 150 μM CsA (n = 16; p = 0.38). (Right) NMDA responses in Rap2(ca)-GFP-expressing cells cultured in media containing 5 μM SP (n = 14; p = 0.33), 5 μM SP for 12 hr followed by normal media for 4–6 hr (n = 14; p = 0.73), 2 μM SB (n = 16; p = 0.35), 25 μM PD98059 (n = 14; p = 0.47), 12 mM Mg2+ (n = 18; p = 0.68), 25 μM FK-506 (n = 14; p = 0.93), or 150 μM CsA (n = 16; p = 0.30). AMPA-R- and NMDA-R-mediated current amplitude and standard errors were normalized to average values from control cells. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

5 Figure 4 Rap2 Activity Stimulates JNK Signaling
(A) Western blots of phospho-p46/54 JNK in control hippocampal CA1 regions, hippocampal CA1 regions expressing Rap2(ca)-GFP, and hippocampal CA1 regions expressing Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (40 μg). (Left histograms) Relative amounts of phospho-p46/54 JNK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 17, p < for phospho-p46 JNK; n = 17, p < 0.01 for phospho-p54 JNK) or Rap2(dn)-GFP (n = 17, p < 0.01 for phospho-p46 JNK; n = 17, p < for phospho-p54 JNK). Relative amounts of total p46/54 JNK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 17, p = 0.60 for p46 JNK; n = 17, p = 0.49 for p54 JNK) or Rap2(dn)-GFP (n = 17, p = 0.76 for p46 JNK; n = 17, p = 0.59 for p54 JNK). (Middle histograms) Relative amounts of phospho-p46/54 JNK in hippocampal CA1 regions expressing Ras(ca)-GFP (n = 19, p = 0.88 for phospho-p46 JNK; n = 19, p = 0.87 for phospho-p54 JNK) or Ras(dn)-GFP (n = 19, p = 0.75 for phospho-p46 JNK; n = 19, p = 0.97 for phospho-p54 JNK). Relative amounts of total p46/54 JNK in hippocampal CA1 regions expressing Ras(ca)-GFP (n = 19, p = 0.42 for p46 JNK; n = 19, p = 0.32 for p54 JNK) or Ras(dn)-GFP (n = 19, p = 0.94 for p46 JNK; n = 19, p = 0.97 for p54 JNK). (Right histograms) Relative amounts of phospho-p46/54 JNK in hippocampal CA1 regions expressing Rap1(ca)-GFP (n = 20, p = 0.48 for phospho-p46 JNK; n = 20, p = 0.77 for phospho-p54 JNK) or Rap1(dn)-GFP (n = 20, p = 0.26 for phospho-p46 JNK; n = 20, p = 0.63 for phospho-p54 JNK). Relative amounts of total p46/54 JNK in hippocampal CA1 regions expressing Rap1(ca)-GFP (n = 20, p = 0.46 for p46 JNK; n = 20, p = 0.58 for p54 JNK) or Rap1(dn)-GFP (n = 20, p = 0.46 for p46 JNK; n = 20, p = 0.60 for p54 JNK). (B) (Left) Western blots of phospho-p42/44 MAPK in control hippocampal CA1 regions, hippocampal CA1 regions expressing Rap2(ca)-GFP, and hippocampal CA1 regions expressing Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (40 μg). (Right) Relative amounts of phospho-p42/44 MAPK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 20, p = 0.72 for phospho-p42 MAPK; n = 20, p = 0.63 for phospho-p44 MAPK) or Rap2(dn)-GFP (n = 20, p = 0.68 for phospho-p42 MAPK; n = 20, p = 0.50 for phospho-p44 MAPK). Relative amounts of total p42/44 MAPK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 20, p = 0.71 for p42 MAPK; n = 20, p = 0.25 for p44 MAPK) or Rap2(dn)-GFP (n = 20, p = 0.24 for p42 MAPK; n = 20, p = 0.42 for p44 MAPK). (C) (Left) Western blots of phospho-p38 MAPK in control hippocampal CA1 regions, hippocampal CA1 regions expressing Rap2(ca)-GFP, and hippocampal CA1 regions expressing Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (40 μg). (Right) Relative amounts of phospho-p38 MAPK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 20; p = 0.66) or Rap2(dn)-GFP (n = 20; p = 0.94). Relative amounts of total p38 MAPK in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 20; p = 0.85) or Rap2(dn)-GFP (n = 20; p = 0.39). The relative values and standard errors were normalized to average amounts of phospho-JNK, phospho-Erk1/2, phospho-p38 MAPK, total JNK, total Erk1/2, or total p38 MAPK from control hippocampal CA1 regions. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

6 Figure 5 Rap2 Activity Controls Long-Term Depotentiation
(A) Average AMPA-R-mediated synaptic responses obtained before (−60 mV; thick trace) and after (−60 mV; thin trace) LTP-depotentiation-inducing pairing from a pair of Rap2(dn)-GFP-expressing and neighboring nonexpressing cells in LTP-depotentiation double paired (upper left) and control pathway (upper right). (Lower plot) Simultaneously evoked responses recorded from the cell pairs expressing or not expressing Rap2(dn)-GFP against time. (B) Normalized simultaneously evoked responses recorded from all cell pairs expressing or nonexpressing Rap2(dn)-GFP against time. (C) Steady-state synaptic AMPA-R-mediated response amplitudes in paired (n = 10; p < 0.01) and control pathways (n = 10; p = 0.28) in cells expressing Rap2(dn)-GFP and neighboring nonexpressing control cells before and after pairing. (D) Average AMPA-R-mediated synaptic responses obtained before (−60 mV; thick trace) and after (−60 mV; thin trace) LTP-depotentiation-inducing pairing from a pair of Rap2(ca)-GFP-expressing and neighboring nonexpressing cells in LTP-depotentiation double paired (upper left) and control pathway (upper right). (Lower plot) Simultaneously evoked responses recorded from the cell pairs expressing or not expressing Rap2(ca)-GFP against time. (E) Normalized simultaneously evoked responses recorded from cells expressing or nonexpressing Rap2(ca)-GFP against time. (F) Steady-state synaptic AMPA-R-mediated response amplitudes in paired (n = 9; p = 0.86) and control (n = 9; p = 0.24) pathways in cells expressing Rap2(ca)-GFP and neighboring nonexpressing control cells before and after pairing. AMPA-R-mediated current amplitude and standard errors were normalized to average initial values from control cells. (G) Normalized simultaneously evoked responses recorded from cells recorded with or without 5 μM SP included in the bath solution, and cells expressing TNIK(dn)-GFP recorded in the normal bath solution against time. (H) Steady-state synaptic AMPA-R-mediated response amplitudes before and after LTP-depotentiation-inducing pairing in cells recorded in the normal bath solution (n = 12; p < 0.001) or in the bath solution with 5 μM SP (n = 12; p = 0.54), or cells expressing TNIK(dn)-GFP recorded in the normal bath solution (n = 8; p < 0.005). AMPA-R-mediated current amplitude and standard errors were normalized to average initial values from cells recorded in the normal bath solution. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

7 Figure 6 Rap2 Removes Synaptic GluR1- and GluR2L-Containing AMPA-Rs
(A) Nonexpressing cells (Ctrl) and cells coexpressing GluR2Lct-GFP with Rap2(ca)-RFP under transmitted light (top) and fluorescence microscopy with either RFP (middle) or GFP (bottom) filter. (B) (Upper) Evoked AMPA-R-mediated (−60 mV) and NMDA-R-mediated (+40 mV) responses recorded from nonexpressing cells (Ctrl) and cells coexpressing GluR2Lct-GFP with Rap2(ca)-RFP. (Lower left) AMPA responses in cells coexpressing GluR2Lct-GFP with Rap2(ca)-RFP (n = 14; p < 0.005) or GluR2ct-GFP with Rap2(ca)-RFP (n = 12; p < 0.005) relative to neighboring nonexpressing control cells. (Lower right) NMDA responses in cells expressing GluR2Lct-GFP with Rap2(ca)-RFP (n = 14; p = 0.36) or GluR2Lct-GFP with Rap2(ca)-RFP (n = 12; p = 0.06) relative to neighboring nonexpressing control cells. (C) Evoked AMPA-R-mediated (−60 mV) responses and rectification recorded from neighboring cell triples including a nonexpressing cell (Ctrl), a GluR2(R→Q)-GFP-expressing cell, and a GluR2(R→Q)-GFP and Rap2(ca)-RFP-coexpressing cell. (D) (Left) AMPA responses in cells expressing GluR2(R→Q)-GFP and cells coexpressing GluR2(R→Q)-GFP with Rap2(ca)-RFP (n = 12; p = 0.58 for Ctrl versus exp; p < 0.05 for Ctrl versus co-exp), cells coexpressing GluR2L(R→Q)-GFP with Rap2(ca)-RFP (n = 14; p < 0.005), or cells coexpressing GluR1-GFP and Ras(ca)-GFP with Rap2(ca)-RFP (n = 16; p < 0.01) relative to neighboring nonexpressing control cells. (Right) Rectification of AMPA-R-mediated responses in cells expressing GluR2(R→Q)-GFP and cells coexpressing GluR2(R→Q)-GFP with Rap2(ca)-RFP (n = 12; p < 0.01 for Ctrl versus exp; p < for Ctrl versus co-exp), cells coexpressing GluR2L(R→Q)-GFP with Rap2(ca)-RFP (n = 14; p = 0.64), or cells coexpressing GluR1-GFP and Ras(ca)-GFP with Rap2(ca)-RFP (n = 16; p = 0.72) relative to neighboring nonexpressing control cells. (E) Evoked AMPA-R-mediated (−60 mV) responses recorded from neighboring cell triples including a nonexpressing cell (Ctrl) and two Rap2(ca)-GFP-expressing cells, loading with either G10 or S10. (F) Normalized simultaneously evoked responses recorded from all cell triples expressing or nonexpressing Rap2(ca)-GFP against G10 or S10 loading time. (G) Residual AMPA responses obtained 30 min after loading G10 or S10 from cell triples expressing and nonexpressing Rap2(ca)-GFP (n = 12; p < for Ctrl/G10 versus exp/G10, Ctrl/G10 versus exp/G10, and exp/G10 versus exp/S10). AMPA-R-mediated current amplitudes, rectification, and standard errors were normalized to average values from control cells. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

8 Figure 7 Rap2 Activity Decreases Phosphorylation of GluR1 and GluR2L Receptors (A) (Left) Western blots of phospho-p841-GluR2L in control hippocampal CA1 regions and hippocampal CA1 regions expressing Rap2(ca)-GFP and Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (40 μg). (Right) Relative amounts of phospho-p841-GluR2L in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 17; p < 0.005) or Rap2(dn)-GFP (n = 17; p < 0.01). Relative amounts of total GluR2L in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 17; p = 0.74) or Rap2(dn)-GFP (n = 17; p = 0.44). (B) (Upper left) Western blots of phospho-p831-GluR1 in control hippocampal CA1 regions and hippocampal CA1 regions expressing Rap2(ca)-GFP and Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (30 μg). (Upper right) Relative amounts of phospho-p831-GluR1 in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 16; p = 0.13) or Rap2(dn)-GFP(n = 16; p = 0.33). Relative amounts of total GluR1 in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 16; p = 0.11) or Rap2(dn)-GFP (n = 16; p = 0.15). (Lower left) Western blots of phospho-p845-GluR1 in control hippocampal CA1 regions and hippocampal CA1 regions expressing Rap2(ca)-GFP and Rap2(dn)-GFP. Each lane was loaded with the same amount of protein (40 μg). (Lower right) Relative amounts of phospho-p845-GluR1 in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 16; p = 0.87) or Rap2(dn)-GFP(n = 16; p = 0.39). Relative amounts of total GluR1 in hippocampal CA1 regions expressing Rap2(ca)-GFP (n = 16; p = 0.99) or Rap2(dn)-GFP (n = 16; p = 0.54). The relative values and standard errors were normalized to average amounts of phospho-p831-GluR1 and phospho-p845-GluR1 or total GluR1 from control hippocampal CA1 regions. (C) (Upper left) Western blots of phospho-p831-GluR1 in hippocampal CA1 regions expressing Ras(ca)-GFP, Ras(ca)-GFP-IRES-Rap2(ca)-RFP, and Ras(ca)-GFP-IRES-Rap2(dn)-RFP. Each lane was loaded with the same amount of protein (30 μg). (Upper right) Relative amounts of phospho-p831-GluR1 in hippocampal CA1 regions expressing Ras(ca)-GFP-IRES-Rap2(ca)-RFP (n = 13; p < 0.01) or Ras(ca)-GFP-IRES-Rap2(dn)-RFP (n = 13; p < 0.01) to neurons expressing Ras(ca)-GFP. Relative amounts of total GluR1 in hippocampal CA1 regions expressing Ras(ca)-GFP-IRES-Rap2(ca)-RFP (n = 13; p = 0.42) or Ras(ca)-GFP-IRES-Rap2(dn)-RFP (n = 13; p = 0.86) to neurons expressing Ras(ca)-GFP. (Lower left) Western blots of phospho-p845-GluR1 in control hippocampal CA1 regions expressing Ras(ca)-GFP, Ras(ca)-GFP-IRES-Rap2(ca)-RFP, and Ras(ca)-GFP-IRES-Rap2(dn)-RFP. Each lane was loaded with the same amount of protein (40 μg). (Lower right) Relative amounts of phospho-p845-GluR1 in hippocampal CA1 regions expressing Ras(ca)-GFP-IRES-Rap2(ca)-RFP (n = 15; p < 0.05) or Ras(ca)-GFP-IRES-Rap2(dn)-RFP (n = 15; p < 0.01) to neurons expressing Ras(ca)-GFP. Relative amounts of total GluR1 in hippocampal CA1 regions expressing Ras(ca)-GFP-IRES-Rap2(ca)-RFP (n = 15; p = 0.87) or Ras(ca)-GFP-IRES-Rap2(dn)-RFP (n = 15; p = 0.65) to neurons expressing Ras(ca)-GFP. The relative values and standard errors were normalized to average amounts of phospho-p831-GluR1 and phospho-p845-GluR1 or total GluR1 from control hippocampal CA1 regions expressing Ras(ca)-GFP. *p < 0.05 (Wilcoxon test). See Supplemental Data for the values. Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions

9 Figure 8 Model for Ras-Erk1/2, Rap1-p38 MAPK, and Rap2-JNK Pathway-Mediated Synaptic Plasticity Neuron  , DOI: ( /j.neuron ) Copyright © 2005 Elsevier Inc. Terms and Conditions


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