(A) Schematic depiction of early D-cycloserine (DCS) treatment and behavioral tests. Young Shank2−/− mice were orally administered D-cycloserine (40 mg/kg) twice daily for two weeks during P7-21, followed by consecutive measurements of open-field hyperactivity and three-chamber social interaction during P56-70. (B and C) Early D-cycloserine treatment fails to improve social interaction of adult Shank2−/− mice, as indicated by time sniffing S1/O and the social preference index based on sniffing time in the three-chamber test. (n = 21 mice for WT-V, 16 (WT-M), 21 (KO-V), and 11 (KO-M), ns, not significant, ***P < 0.001, ns, not significant, paired Student’s t-test or Wilcoxon matched pairs signed rank test (B), Mann Whitney U test (C). (D) Schematic depiction of late chronic memantine treatment and behavioral tests. Shank2−/− mice were orally administered memantine (20 mg/kg) twice daily for 2 weeks during P25-39, followed by consecutive measurements of three-chamber social interaction and open-field hyperactivity during P56-90. (E and F) Late chronic memantine treatment fails to improve social interaction in Shank2−/− mice, as indicated by time sniffing S1/O and the social preference index based on sniffing time in the three-chamber test. (n = 15 (WT-V), 14 (WT-M), 13 (KO-V), and 14 (KO-M), ns, not significant, ***P < 0.001, ns, not significant, paired Student’s t- test or Wilcoxon matched pairs signed rank test (E), unpaired Student’s t-test (F).