Figure 3.
Induction of EEG gamma activity by MRK-016 is absent in mice lacking GABAAR α5 subunits. (A, C) Representative EEG spectrograms showing oscillatory activity normalized to baseline for wildtype and α5 KO mice respectively. More relative activity at a given frequency range is indicated by “warmer” colors, and less by “cooler” colors. (B, D) Representative EEG gamma activity (750ms) at baseline and 30 minutes after treatment, filtered to 30-80Hz. (E) EEG gamma powers (30-80hz) were normalized to the last 30 minutes of baseline gamma activity following DMSO vehicle and MRK-016 administration. MRK-016 produces significantly higher cortical gamma power in wildtypes vs α5 KO animals beginning 20 minutes after administration. 2-way ANOVA identifies significant effect between time × genotype (F 17,238 = 2.678, p=0.0005). (F) There is no significant difference in gamma powers at any time point between wildtype or α5 KO animals in response to ketamine. Time × genotype (F 17,238 = 0.5589, p=0.9193). (G) MRK-016 promotes significant increases in gamma power over a 60-minute period after treatment compared to DMSO vehicle in wildtype (n=9, p=0.0462) but not α5 KO animals (n=7, p=0.9962). Wildtype animals generate significantly more gamma power compared to α5 KOs following MRK-016 administration (p=0.0390). 2-way ANOVA identifies significant effect between treatment × genotype (F 1,14 = 5.052, p=0.0412). (H) Normalized EEG gamma power quantified for 60 minutes after 10mg/kg (R,S) ketamine (i.p.) administration was significantly greater than after volume-equivalent saline vehicle for both wildtype (n=9, p=0.0033) and α5 KO cohorts (n=7, p=0.0027). 2-way ANOVA identifies significant treatment effect (F 1,14 = 28.35, p=0.0001), but no significant interaction between treatment × genotype (F 1,14 = 0.4164, p=0.5292). p<0.05 *, p<0.005 ***.