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. 2020 Mar 6;9:e54224. doi: 10.7554/eLife.54224

Figure 6. Presynaptic PTPσ-dependent regulation of postsynaptic NMDARs is important for novelty recognition in Emx1-Cre;Ptprsfl/fl mice.

Figure 6.

(A) D-cycloserine (DCS) treatment (20 mg/kg; i.p.) rescues social-novelty recognition in Emx1-Cre;Ptprsfl/fl mice (2–3 months) without affecting social approach. Note that DCS has no effect on social approach or novelty recognition in WT mice. (n = 13, 14, 14, 14 mice for WT-V/vehicle, WT-D/D-cycloserine, cKO-V, cKO-D, *p<0.05, **p<0.01, ***p<0.001, ns, not significant, two-way ANOVA with Sidak’s test). (B and C) Impaired social-novelty recognition in Ptprsfl/fl mice injected with AAV1-hSyn-Cre-eGFP in the CA3 region, but not the CA1 region, in the three-chamber test compared with control Ptprsfl/fl mice injected with AAV1-hSyn-ΔCre-eGFP in CA3 or CA1 regions. Note that social approach (left panel) is unaffected by either CA3- or CA1-specific PTPσ KO. EGFP fluorescence indicates virus injection sites in CA3/CA1 regions. (n = 13, 11, 15, 14 mice for CA3-EGFP, CA3-Cre, CA1-EGFP and CA1-Cre, respectively, *p<0.05, **p<0.01, ***p<0.001, ns, not significant, two-way ANOVA with Sidak’s test). (D) Impaired recognition of novel, but not initial, reward-arm location in Ptprsfl/fl mice injected with AAV1-hSyn-Cre-eGFP in the CA3, but not CA1, region in the Y-maze test (3 months), compared with control Ptprsfl/fl mice injected with AAV1-hSyn-ΔCre-eGFP. (n = 9, 7, 16, 17 mice for CA3-EGFP, CA3-Cre, CA1-EGFP and CA1-Cre, respectively, during learning phase, n = 6, 3, 13, 11 mice for reversal phase, two-way ANOVA with Sidak’s test) (E and F) Knockdown of the GluN1 subunit of NMDARs in the CA1 region of WT mice (C57/BL6J) by injection of AAV(php.eB)-pU6-shGluN1 suppresses social-novelty recognition but not social approach, a finding that contrasts with the normal social-novelty recognition observed in control WT mice injected with AAV(php.eB)-pU6-shCtrl (scrambled control). (n = 13, 11 mice for shCtrl and shGluN1, respectively, **p<0.01, ***p<0.001, ns, not significant, two-way ANOVA with Sidak’s test). (G) GluN1 knockdown in the CA1 region of WT mice (C57/BL6J) by injection of AAV(php.eB)-pU6-shGluN1 suppresses novel, but not initial, reward-arm recognition compared with control WT mice injected with AAV(php.eB)-pU6-shCtrl. (n = 17 [shGluN1-initial], 19 [shCtrl-initial], 15 [shGluN1-reversal], 15 [shCtrl-reversal], **p<0.01, ***p<0.001, ns, not significant, RM two-way ANOVA with Sidak’s test). (H) Validation of AAV(php.eB)-pU6-shGluN1/shCtrl viruses by immunoblot analysis of the GluN1 protein from the injected hippocampus. GluN1 levels were normalized to α-tubulin levels. (n = 3, three mice for ShCtrl and shGluN1, *p<0.05, one sample t-test).