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. 2018 Jan 10;43(6):1457–1465. doi: 10.1038/npp.2017.295

Figure 2.

Figure 2

Positive allosteric modulation of mGluR5 exacerbates hyperactivity and seizures in Tsc2-deficient mice. (ai) Chemical structure and composition of the mGluR5 PAM RO6807794. (aii) Tsc2-deficient mice (KC+ N=8 PAM and 9 VEH) travel significantly greater total distances than control mice (N=9 PAM and 13 VEH) in the open-field assay and PAM treatment significantly increases that distance in KC+ but not control mice (two-way repeated measures ANOVA, group × time F(42,490)=2.726, p<0.0001; group F(3,35)=3.908, p=0.017; time F(14,490)=37.26, p<0.0001). Subplot indicates pattern of locomotor activity. (aiii) KC+ enter the center zone of the open field significantly more frequently than control mice, and PAM treatment significantly increases the number of entries in the KC+ but not control mice (two-way ANOVA, genotype × treatment, genotype F(1,41)=29.45, p<0.0001; treatment F(1,41)=11.36, p=0.002). (b) Representative EEG traces from wireless telemetry (i) spontaneous seizure activity in mutants, (ii) acute PAM treatment led to a long clinical seizure in mutants. (iii) PAM administration resulted in a significant increase in the fraction of clinical seizures, from 3.6% at baseline to 68% post treatment (N=7 KC+ PAM, paired t-test, p=0.02). (c) Acute PAM administration significantly exacerbated both seizure frequency (Kruskal–Wallis ANOVA, p=0.0021) and total seizure time (Kruskal–Wallis ANOVA, p=0.0004) in KC+ mice in 2 h following treatment. PAM-treated KC+ had significantly more seizures (p=0.01) and significantly longer seizures (p=0.003) than PAM-treated control mice, as compared by Dunn’s post hoc tests. PAM-treated KC+ animals also had significantly more seizures than VEH-treated KC+ animals (p=0.04). There was no effect of PAM treatment on control animals (N=6 control VEH, 6 control PAM, 7 KC+ VEH, and 7 KC+ PAM). Data are plotted as mean±SEM. *p<0.05, **p<0.01, ****p<0.0001.