(A) Early memantine treatment (P7-21) normalizes the NMDA/AMPA ratio at juvenile (~P25-31) Shank2−/− SC-CA1 synapses. Young Shank2−/− mice were orally administered memantine (20 mg/kg) twice daily for 2 weeks during P7-21 followed by measurements of NMDA/AMPA ratio at ~P25-31. (n = 22 neurons from 9 mice for WT- V, 19 (6) for WT-M, 18 (9) for KO-V, and 13 (3) for KO-M, *P < 0.05, ns, not significant, two-way ANOVA with Holm-Sidak test). (B and C) Early memantine treatment (P7-21) normalizes LTP induced by high- frequency stimulation at juvenile (~P25-31; B) and adult (> P56; C) Shank2−/− SC-CA1 synapses. Numbers 1 and 2 indicate fEPSP slopes during the baseline and last 5-min recordings, respectively. (Juvenile, n = 12 slices from 6 mice for WT-V, 10 (5) for WT-M, 16 (8) for KO-V, and 14 (8) for KO-M; adult, n = 18 (9) for WT-V, 25 (12) for WT-M, 23 (9) for KO-V, and 20 (7) for KO-M, **P < 0.01, ***P < 0.001, ns, not significant, two-way ANOVA with Holm-Sidak test). (D) Early memantine treatment for a shorter period (P7-14; 20 mg/kg oral/day) normalizes the NMDA/AMPA ratio at ~P15 at Shank2−/− SC-CA1 synapses. (n = 14 neurons from 8 mice for WT-V, 14 (4) for WT-M, 12 (7) for KO-V, and 11 (6) for KO-M, *P < 0.05, **P < 0.05, two-way ANOVA).