Fig. 4: CA3 localized PSEN2 is required for hippocampal circuitry and LTP. | Nature Communications

Fig. 4: CA3 localized PSEN2 is required for hippocampal circuitry and LTP.

From: Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits

Fig. 4

a Representative confocal images of PSEN2 immunoreactivity in coronal sections of hippocampus from wild-type, PSEN2KO and FADPSEN2 mice; quantified in (b) as a CA3/CA1 ratio. Wild type, N(number of mice)=4, n(total slices analyzed)=12, PSEN2KO N = 4 n = 12, FADPSEN2 N = 4, n = 7. Statistical analysis was performed using one-way ANOVA with Dunnet’s correction for multiple testing compared to wild type. c Representative images from the hippocampal CA3 region of wild-type, PSEN2KO and FADPSEN2 mice immunostained for PSEN2, ZNT3 and PSD95. Representative images were selected from 3 different mice stained per genotype. d Schematic of the recording and stimulating electrodes. Created in BioRender. Vrancx, C. (2024) https://BioRender.com/j96p125. e fEPSPs recorded from mossy fiber-CA3 synapses in 6 month old wild-type, APPKI, APPxPSEN2KO and APPxFADPSEN2 mice. After 30 min of baseline recordings, LTP was induced by two trains of 75hz stimulation and fEPSPs recorded for 50 min. e LTP amplitude. f LTP slope. For both amplitude and slope wild type N = 5, APPNLGF N = 5, APPxPSEN2KO N = 5, APPxFADPSEN2 N = 5 where N represents individual mice. g Average amplitude for the last four triplicate fEPSPs compared to wild-type. Statistical analysis was done using a one-way ANOVA with Dunnett’s test for multiple comparisons. h Representative traces from paired pulse recordings in CA1 plotted with 40 ms interval. Double line is used to indicate additional time passing. i Paired pulse results from the CA1 region represented as %amplitude from the first recorded amplitude. Number of mice (N) and cells (n) recorded: Wild type N = 5 n = 10, APPKI N = 5 n = 9, APPxPSEN2KO N = 5 n = 10, APPxFADPSEN2 N = 5 n = 9. j Representative traces from paired pulse recordings in CA3 plotted with 40 ms interval. Double line is used to indicate additional time passing. k Paired pulse results from the CA3 region represented as %amplitude. Statistical analysis was performed per interval using a one-way ANOVA with Dunnett’s correction for multiple testing comparing genotypes to wild type. Exact pvalues: 20 ms****=<0.0001, 40 ms***=0.0003, 60 ms*=0.0338, ****=< 0.0001, 80 ms*=0.0204, ***=0.0001, 100 ms*=0.0380, ***=0.0003, 200 ms*=0.0285, ***=0.0006, 400 ms***=0.0003, 800 ms**=0.0011, 1000 ms****=<0.0001, 2000ms****=<0.0001. Number of mice (N) and cells (n) recorded: Wild type N = 3 n = 5, APPKI N = 4 n = 5, APPxPSEN2KO N = 5 n = 7, APPxFADPSEN2 N = 3 n = 4. l–o Train stimulation data for the CA1 and CA3 respectively with each graph representing a different stimulus strength. Response is calculated as % of the total first response with increasing paired pulse interval. Statistical analysis was performed per interval using a one-way ANOVA with Dunnett’s correction for multiple testing, always comparing to wild type. Exact p-values CA1 1 Hz 3 ms*=0.0256, 4 ms*=0.0430, 6 ms*=0.0282, 7 ms*=0.0484. CA1 20 Hz 0.1 ms*=0.0117, 0.15 ms*=0.0137, 0.25 ms**=0.0087, 0.3 ms*=0.0218. CA3 1 Hz 1 ms**=0.0015, 2 ms***=0.0006, 3 ms***=0.0007, 4 ms****=<0.0001, 5 ms***=0.0001, 6 ms***=0.0001, 7 ms***=0.0001, 8 ms***=0.0007, 9 ms***=0.0008. CA3 20 Hz 0.05 ms***=0.0007, 0.1 ms**=0.0022, 0.15 ms***=0.0008, 0.2*** = 0.0005, 0.25** = 0.0039, 0.3 ms***=0.0007, 0.35 ms**=0.0012, 0.4 ms*=0.0297, 0.45* = 0.0432. Number of mice (N) and cells (n) recorded for CA1: Wild-type N = 5 n = 10, APPKI N = 5 n = 9, APPxPSEN2KO N = 5 n = 10, APPxFADPSEN2 N = 5 n = 9. Number of mice (N) and cells (n) recorded for CA3: Wild-type N = 5 n = 9, APPKI N = 4 n = 5, APPxPSEN2KO N = 5 n = 7, APPxFADPSEN2 N = 3 n = 4. All graphs are represented as mean ± SEM and include p-values.

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