Fig. 2. Inhibition of PKR rescues the deficits in long-term memory and synaptic plasticity in Ts65Dn mice.

(A and B) Representative immunoblot (A) and quantification (B) of eIF2-P levels in hippocampal extracts from WT (n = 9), Ts65Dn (n = 10), and Ts65Dn-Pkr^−/− mice [n = 7, F_2,23 = 4.12, one-way analysis of variance (ANOVA)]. (C and D) Incorporation of puromycin into nascent peptides was detected using an anti-puromycin antibody. A representative immunoblot (C) and quantification (D) in hippocampal extracts from WT (n = 8), Ts65Dn (n = 7), and Ts65Dn-Pkr^−/− mice (n = 6, F_18,2 = 25.16). (E) Schematic of the fear conditioning paradigm. (F) Genetic inhibition of PKR: freezing behavior before (naïve) and 24 hours after training in WT (n = 12), Ts65Dn (n = 10), and Ts65Dn-Pkr^−/− mice (n = 9, H = 22.74, one-way ANOVA on ranks). (G) Pharmacological inhibition of PKR: freezing behavior before (naïve) and 24 hours after training in vehicle-treated (n =15) and PKRi-treated Ts65Dn mice (n = 14, t₂₇ = 3.21). (H) Schematic of the object recognition task. (I) Genetic inhibition of PKR: novel object discrimination index 24 hours after training in WT (n = 15), Ts65Dn (n = 15), and Ts65Dn-Pkr^−/− mice (n = 12, F_2,39 = 11.56). (J) Pharmacological inhibition of PKR: novel object discrimination index 24 hours after training in vehicle-treated (n = 10) and PKRi-treated Ts65Dn mice (n = 12, t₂₀ = 3.48). (K) Genetic inhibition of PKR: L-LTP induced by four trains of high frequency stimulation (HFS, 4 × 100) in WT (n = 10), Ts65Dn (n = 14), and Ts65Dn-Pkr^−/− mice (n = 14, H = 15.72, P < 0.05). fEPSP, field excitatory postsynaptic potential. (L) Pharmacological inhibition of PKR: L-LTP induced by 4 × 100 Hz of HFS in vehicle-treated (n = 7) and PKRi-treated Ts65Dn mice (n = 13, U = 41.00, P < 0.05, Mann-Whitney U test). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.