Figure 4. Genetic cross of Tsc2+/− and Fmr1−/y mice rescues synaptic and behavioral impairments present in both single mutants.
(A) The data suggest that optimal synaptic function requires a narrow and tightly regulated level of synaptic protein synthesis and that deviations in either direction can impair function3,43. TSC and FXS fall on different ends of this spectrum and respond to opposite alterations of mGluR5 signaling. These results raise the possibility that introducing both mutations to a mouse may normalize aspects of neural function. (B) Genetic rescue strategy. Heterozygous Tsc2 male mice (Tsc2+/−) were bred with heterozygous Fmr1 females (Fmr1 x+/x−) to obtain male offspring of four genotypes: wild type (Tsc2+/+, Fmr1+/y), Fmr1 KO (Tsc2+/+, Fmr1−/y), Tsc2 Het (Tsc2+/−, Fmr1+/y), and Cross (Tsc2+/−, Fmr1−/y). (C) DHPG-induced LTD is significantly decreased in slices from Tsc2+/− mice (*p = 0.002) and significantly increased in slices from Fmr1−/y mice (*p = 0.017), as compared to WT slices. DHPG-LTD in slices from Tsc2+/− × Fmr1−/y mice is comparable in magnitude to WT slices (p = 0.558). (WT: 78.9 ± 2.1%, n = 7 animals, 17 slices; Fmr1: 71.2 ± 2.7%, n = 7 animals, 21 slices; Tsc2: 89.5 ± 2.6%, n = 7 animals, 15 slices; Cross: 77.4 ± 1.8%, n = 9 animals, 19). (D) Summary of LTD data. Bar graphs represent percent decrease from baseline in fEPSP (average of last 5 minutes of recording ± SEM); *p < 0.05, **p < 0.01. (E) Both mutations cause a deficit in context discrimination that is rescued in the double mutant. WT mice (Familiar: 42.9 ± 4.6%, n = 11; Novel: 27.8 ± 3.4%, n = 12; *p = 0.024), Fmr1−/y mice (Familiar: 49.0 ± 5.6%, n = 11; Novel: 43.5 ± 6.7%, n = 12; p = 0.483), Tsc2+/−(Familiar: 42.1 ± 6.8%, n = 12; Novel: 35.6 ± 6.0%, n = 12; p = 0.395) and Tsc2+/− x Fmr1−/y mice (Familiar: 50.5 ± 5.2%, n = 11; Novel: 29.8 ± 5.2%, n = 11; *p = 0.011). Error bars represent SEM.