(A) Representative images from Sindbis-mediated viral expression of C99ΔC in CA1 neurons in OTSCs. The time-dependent dendritic spine loss can be blocked by the addition of 10 μM γ-secretase inhibitor (GSI) to inhibit Aβ production. Scale bar, 20 μm. (B) Quantification of spine density from (A) showed significant spine loss starting at 18 h post-infection and decreased to a maximum of ~50% at 24 h post-infection. Addition of GSI at 12 h and 18 h post-infection attenuated synapse loss, with the greatest effect when treatment was started at 12 h, where spine numbers were comparable to control slices not infected with C99ΔC. control tdTomato-infected culture: n = 15 neurons; C99ΔC-infected cultures: 15 neurons (12 h), 8 neurons (18 h), 14 neurons (24 h); GSI-treated cultures: n = 9 neurons (12 h), 11 neurons (18 h) from a total of 21 mice for all experiments in aggregate NS, not significant, *p ≤ 0.05, ***p ≤ 0.001, ****p ≤ 0.0001 by two-way ANOVA followed by Tukey’s multiple comparisons test.