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, 56 (6), 955-62

Correction of Fragile X Syndrome in Mice


Correction of Fragile X Syndrome in Mice

Gül Dölen et al. Neuron.


Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.


Figure 1
Figure 1. Genetic rescue of OD plasticity phenotype in FXS
(A) Schematic of the mouse visual pathway and position of the recording electrode in primary visual cortex. (B) Absolute VEP amplitudes recorded during binocular viewing across contrasts (0 –100%, square reversing at 1 Hz, 0.05 cycles/degree). No significant differences across genotypes. (n = 46 WT, n = 33 KO, n = 8 HT, n = 20 CR hemispheres, MANOVA P = 0.0868). (C) Effect of 3 day MD on VEP amplitude (data expressed as mean ± SEM, normalized to day 0 ipsilateral eye value. (C1) WT mice (n = 19). Note significant deprived eye depression. (C2) KO mice (n = 18). Note significant open eye potentiation. (C3) HT mice (n = 16). Note absence of deprived eye depression. (E4) CR mice (n = 13). Note rescue of KO phenotype. Post-hoc t-tests: * indicates significantly different from baseline (day 0). (D) Plots (mean ± SEM) of the fractional change in open and deprived eye responses after 3 day MD show rescue of the KO phenotype in CR mice.
Figure 2
Figure 2. Genetic rescue of dendritic spine phenotype in FXS
(A) Representative images from apical (A1) and basal (A2) dendritic segments of layer 3 pyramidal neurons in the binocular region of primary visual cortex of all four genotypes collected at P30. (B) Cumulative percent spines per μm in each dendritic segment; apical branches, B1; basal branches, B2 (n = 80 WT, 80 KO, 60 HT, 80 CR apical and basal branches, respectively). (C) Segmental analysis of spine density; number of spines per 10 μm bin, given as distance from the origin of the branch, for apical (C1) and basal (C2) segments across four genotypes.
Figure 3
Figure 3. Genetic rescue of protein synthesis phenotype in FXS
(A) Significant differences in the levels of protein synthesis exist across genotypes in the ventral hippocampus (n = 10 samples, 5 animals per genotype). KO mice showed increased protein synthesis (mean ± SEM: WT 389 ± 33.77 cpm/μg; KO 476 ± 29.98 cpm/μg; post-hoc paired t-test WT:KO P = 0.004). Protein synthesis levels in the HT mice were no different than WT (HT 409 ± 42.99 cpm/μg). Increased protein synthesis seen in the KO were rescued in the CR mice (CR 374 ± 50.81 cpm/μg). Post-hoc paired t-tests: * indicates significantly different from WT, † indicates significantly different from KO. (B) Representative autoradiogram shows that synthesis of many protein species is elevated in the KO compared to all other genotypes.
Figure 4
Figure 4. Genetic rescue of behavioral learning and memory phenotype in FXS
(A) Experimental design. Animals of all 4 genotypes (n = 15 WT, n = 15 KO, n = 20 HT, n = 17 CR) were given IA training at time 0 and the latency to enter the dark side was measured at 6 h. They were then given IAE training, and latency was again measured at 24 h. Testing was followed by another round of IAE training, and latency was measured again at 48 h. (B) Animals in all four genotypes showed significant acquisition and extinction. Post-hoc t-tests: * indicates significantly different from time 0h, † indicates significantly different from time 6h. (C) Raw data for acquisition of IA in the four genotypes. Each line represents the change in latency to enter the dark side for one mouse (data from some mice superimpose). (D) Raw data for extinction-1 in the four genotypes. (E) Comparison of latency (mean ± SEM) across genotypes for 6 hour time point (post acquisition) and 24 hour time point (post extinction 1). Post-hoc t-tests: * indicates significantly different from WT, † indicates significantly different from KO. (F) Multivariate analysis of extinction as a function of acquisition at 24 h time point (post extinction-1) and 48 h time point. Plotted are mean latencies ± SEM.

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