Hyperexcitability phenotype and seizure-induced effect on cognition in 5XFAD mice. (A) Experimental design in wild-type (WT) and 5XFAD mice involving PTZ kindling starting from 3 months, cognitive assessment from 6.5–7 months and euthanasia for biochemical analyses of the hippocampus at 7 months. The schematic provides additional background on the 5XFAD mice: amyloid-β42 accumulation starting from 1.5 months of age, epileptiform spikes and cognitive impairment starting from 4 months and neuronal and synaptic loss starting from 9 months. (B) Maximal Racine score reached per day of PTZ injection. (C) Maximal Racine score reached per minute during the 1-h post-PTZ injection video recording (average of eight PTZ injections). Inset represents evaluation of the area under the corresponding generated curves. (D) Latency to seizure in minutes. (E) Associative long-term (tested at 24 h post-training) and remote memory (tested at 14 days post-training) assessed with contextual fear conditioning test, measuring % of time freezing adjusted by individual baseline freezing on training day. (F) Spatial working memory evaluated by % spontaneous alternation in the Y-maze. (G) Mice self-care assessed by nest building. Box and whisker plots display minimum, maximum and all quartiles. n = 19 WT-vehicle, 17 WT-PTZ, 12 5XFAD-vehicle and 17 5XFAD-PTZ. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. #Genotype effect, P < 0.01; †Kindling effect, P < 0.05; ††Kindling effect, P < 0.0001.
