(A) In the upper left corner, we show a comparison of representative whole-cell patch-clamp recordings of pharmacologically-isolated NMDAR EPSCs, normalized to the peak amplitude (in %), from GFP (black line) and AICD-NLS (grey line) neurons, illustrating differences in deactivation kinetics. The other three panels show scatter dot plot graphs with the τfast, τslow and τweighted constants, respectively, for NMDAR EPSC deactivation time course in GFP and AICD-NLS neurons before (control; CTR) and after ifenprodil (Ifen; 5 μM) application. (B) Time course of ifenprodil effect on NMDAR EPSC amplitude. Traces show sample EPSCNMDAR recorded before (black trace) and after 40 min of Ifenprodil (5 μM) perfusion (grey trace) in GFP and AICD-NLS neurons. (C) Time course of ifenprodil effect on NMDAR EPSC amplitude in hippocampal slices incubated with vehicle, TAT-AICD-NLS (100 nM) and TAT-scrAICD-NLS (100 nM). Traces show sample EPSCNMDAR recorded before (black trace) and after 40 min of Ifenprodil (5 μM) perfusion (grey trace) in vehicle and TAT-AICD-NLS neurons. (D) Effect of ifenprodil (5 μM) on hippocampal slices pre-incubated with different concentrations of TAT-AICD-NLS (0, 10, 30 and 100 nM). The line represents the nonlinear regression analysis of the data, with IC50 ~13.88 ± 1.65 nM. (E) Bars graph showing the contribution of GluN2B-NMDARs for the EPSCNMDAR at PND 32–40 in different conditions, as indicated. (F) Representative immunoblot of samples of N2a cells WT or KO for APP (APPKO). APP was detected by antibody against C-terminal domain (Y188) and actin was used as loading control. (G) Representative example of N2a-WT and N2a APPKO cells immunostained for APP with Y188. Nuclei were stained with DAPI. (H) Representative example of N2a-APPKO cells, pre-incubated with TAT-AICD-NLS or TAT-AICD-NES for one hour were immunostained for APP with Y188. Nuclei were stained with DAPI. (I) The ratio of mean APP fluorescence in nucleus/cytoplasm was quantified in N2a-APPKO cells pre-incubated with either TAT-AICD-NLS (n = 55) or TAT-AICD-NES (n = 50). Each dot in B, C, D represents one single neuron. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. Full statistical analysis is detailed in Supplementary file 1 .