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. 2024 Jul 10;10(28):eadk5462. doi: 10.1126/sciadv.adk5462

Fig. 7. Reduced presynaptic GBR inhibition in Ajap1−/− and Ajap1W183C/+ mice.

Fig. 7.

(A) Baclofen-induced inhibition of sEPSC amplitude and frequency in HMCs, with representative traces and bar graphs depicting quantitative analysis. n.s., P > 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, one-way ANOVA, Tukey’s multiple comparisons test (amplitude); Kruskal-Wallis test, Dunn’s multiple comparisons test (frequency); n = 16 to 24 cells from ≥3 mice per genotype. (B) Baclofen-induced inhibition of sIPSC amplitude and frequency in HMCs, with representative traces and bar graphs depicting quantitative analysis. n.s., P > 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, one-way ANOVA, Tukey’s multiple comparisons test (amplitude); Kruskal-Wallis test, Dunn’s multiple comparisons test (frequency); n = 12 to 15 cells from ≥3 mice per genotype. Combined traces from Ajap1+/+ littermates of Ajap1−/− and Ajap1W183C/+ mice were used for statistical analysis of sEPSCs and sIPSCs. (C) Time course of fEPSP slopes (mean ± SEM) from hippocampal slices of Ajap1−/− (blue, n = 8 slices from six mice), Ajap1W183C/+ (orange, n = 8 slices from three mice), and Ajap1+/+ mice (black, n = 7 slices from five mice). Arrow indicates the time of theta-burst stimulation (TBS). Sample traces of fEPSPs before (black, blue, and orange) and after (gray) TBS are shown. Ajap1+/+ littermates of Ajap1−/− and Ajap1W183C/+ mice were pooled. Bar graph shows fEPSP slope 60 min after LTP induction normalized to baseline for the different genotypes. *P < 0.05, *P < 0.01, one-way ANOVA, Tukey’s multiple comparisons test. (D) Monoallelic AJAP1-W183C patient variant induces synaptopathy. Left: AJAP1 trans-synaptically recruits presynaptic GBRs by interacting with GB1a. NAM activity of AJAP1 limits constitutive GBR activity at high receptor density. Middle: Complete AJAP1 loss decreases presynaptic GBRs. Right: AJAP1-W183C fails to bind GB1a, reducing presynaptic GBRs. The reduction in presynaptic GBRs induced by the complete lack of AJAP1 or the AJAP1-W183C variant disinhibits neurotransmitter release and impairs synaptic plasticity.