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. Author manuscript; available in PMC: 2007 Dec 7.
Published in final edited form as: Neuron. 2006 Dec 7;52(5):831–843. doi: 10.1016/j.neuron.2006.10.035

Figure 3. Aβ-induced synaptic depression requires p38 MAPK and calcineurin activity.

Figure 3

(A) AMPA and NMDA EPSCs recorded from pairs of non-infected or APP infected CA1 pyramidal neurons. Slices maintained in culture with vehicle (normalized to control (pA): AMPA: control: 1.0±0.06(42.5±2.7), APP: 0.63±0.06(26.9±2.4), n=22, p<0.01 ; NMDA: control: 1.0±0.14(42.1±6.0), APP: 0.64±0.11(27.1±4.5), n=19, p<0.01), p38 MAPK inhibitor, SB203580(2μM) (AMPA: control: 1.0±0.09(37.4±3.3), APP: 0.87±0.07(32.5±2.6), n=19, p=0.14; NMDA: control: 1.0±0.14(15.5± 2.2), APP: 1.02±0.18(15.9±2.7), n=19, p=0.9), calcineurin inhibitor, FK506(50μM) (AMPA: control: 1.0±0.16(37.3±6.1), APP: 1.2±0.11(45.1±4.0) n=9, p=0.2; NMDA: control: 1.0±0.11(25.0±2.8), APP: 0.99±0.17(24.6±4.2), n=9, p=0.95) or JNK inhibitor, SP600125(5μM) (AMPA: control: 1.0±0.2(57.6±11.7), APP: 0.52±0.08(29.7±4.6), n=11, p=0.01; NMDA: control: 1.0±0.16(47.8±7.7), APP: 0.64±0.11(30.6±5.6), n=11, p<0.01). p values from Wilcoxon test. Scale: 20pA, 20ms

(B) Results with cells expressing β-CTF. (Vehicle: AMPA: control: 1.0±0.15(43.9±6.4), β-CTF: 0.51±0.10(22.4±4.3), n=16, p<0.01; NMDA: control: 1.0±0.10(29.1±3.0), β-CTF: 0.78 ± 0.09(22.7±2.6), n=15, p<0.01; SB203580: AMPA: control: 1.0±0.14(29.4±4.1), β-CTF: 0.93±0.15(27.5±4.5), n=16, p=0.4; NMDA: control: 1.0±0.14(11.1±5.9), β-CTF: 1.05±0.15(11.6±1.6), n=15, p=0.6, FK506: AMPA: control: 1.0±0.17(32.4±5.7), β-CTF: 1.01±0.14(32.8±4.5), n=11, p=0.6; NMDA: control: 1.0±0.29(23.4±6.9), β-CTF: 0.98±0.22(23.1±5.2), n=10, p=0.8). p values from Wilcoxon test. Scale: 20pA, 20ms

(C,D) Incubation of transgenic APPSwe mouse hippocampal slices with p38 MAPK inhibitor (SB203580) does not affect Aβ40 or Aβ42 secretion (in pM: Vehicle: Aβ40: 2859±158, Aβ42: 194±12.5; SB203580: Aβ40: 3135±122, p=0.2, Aβ42: 211±9.0, p=0.3, n=4 for each condition) while calcineurin/PP2B inhibitor (FK506) slightly decreases Aβ40 and increases Aβ42 secretion (in pM: Vehicle: Aβ40: 3285±203, Aβ42: 162±10.0; FK506: Aβ40: 2626±216, p=0.04, Aβ42: 287±18.3, p<0.01, n=9 for each condition). A gamma secretase inhibitor (L-685,458, 2μM) decreases Aβ40 levels (in pM: for SB203580 trial: Aβ40: 1767±130, p<0.01, Aβ42: 175±5.6, p=0.2; for FK506 trial: Aβ40: 2049±208, p<0.001, Aβ42: 174±9.3, p=0.5). p values from t-test.

(E) Sample traces of mEPSCs recorded in vehicle, p38 MAPK inhibitor (SB203580) and calcineurin/PP2B inhibitor (FK506). Scale: 20pA, 0.25s.

(F) p38 MAPK inhibitor (SB203580) increases mEPSC frequency, while calcineurin/PP2B inhibitor (FK506) increases mEPSC frequency and amplitude (Frequency (Hz): Vehicle: 0.18±0.02, n=16, SB203580: 0.28±0.03, n=16, p=0.01, FK506: 0.29±0.03, n=16, p<0.01)(mEPSC amplitude (pA): Vehicle: 14.0±0.5, n=16, SB203580: 15.7±0.7, n=16, p=0.07, FK506: 17.3±0.9, n=16, p<0.01). p values from t-test. All data are reported as mean ± SEM. *=p<0.05. **=p<0.01.