Fig. 2
Chemogenetic inhibition of dCA1 PNs improves cognitive functions of hAPP-J20 mice. (A) A representative image showing the expression of the AAV virus microinjected into the dCA1 of J20/CaMKIIα-Cre mice, red: mCherry, blue: DAPI. Scale bar, 500 μm. (B) Representative traces of action potentials recorded in dCA1 PNs before (baseline) and after bath application of CNO (10 µM) and washout of CNO. (Red traces represent the rheobase). (C) The rheobase of dCA1 PNs was higher after CNO treatment (n = 11 cells from 4 mice). Unpaired t-test: t (10) = 3.231, p = 0.0090. **p < 0.01. (D) The numbers of spikes generated in dCA1 PNs in response to depolarizing current injections were significantly decreased after CNO treatment (n = 14 cells from 5 mice). Two-way ANOVA: drug (CNO), F (1, 13) = 24.93, p = 0.0002; current step, F (10, 130) = 125.5, p < 0.0001; interaction, F (10, 130) = 2.957, p = 0.0022; **p < 0.01, ***p < 0.001 with Bonferroni’s post-hoc test. (E) A summary plot in response to 100 pA depolarizing current step showing a significant decrease in the excitability of dCA1 PNs after CNO treatment (n = 10 cells from 4 mice). One-way ANOVA with Bonferroni’s post-hoc test: F (1.77, 15.93) = 15.97, p = 0.0002. **p < 0.01. (F) Path traces of mice and the percentage of alternations in Y-maze test from hAPP-J20 mice expressing mCherry or hM4Di after CNO administration (mCherry, n = 9; hM4Di, n = 9). hAPP-J20 mice expressing hM4Di showed the increased alternations. Unpaired t-test: t (16) = 3.873, p = 0.0013. **p < 0.01. (G) The total arm entries of Y-maze test from hAPP-J20 mice expressing mCherry or hM4Di after CNO administration (mCherry, n = 9; hM4Di, n = 9). Unpaired t-test: t (16) = 0.1362, p = 0.8934. (H) The sociability in three chamber tests from hAPP-J20 mice expressing mCherry or hM4Di after CNO administration (mCherry, n = 9; hM4Di, n = 9). Unpaired t-test: t (16) = 1.905, p = 0.0749. (I) The social novelty in three chamber tests from hAPP-J20 mice expressing mCherry or hM4Di after CNO administration (mCherry, n = 13; hM4Di, n = 9). hAPP-J20 mice expressing hM4Di displayed an increased discrimination index compared with hAPP-J20 mice expressing mCherry. Unpaired t-test: t (20) = 2.107, p = 0.0479. *p < 0.05