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Results: 8

1.
Figure 6

Figure 6. Social anxiety in Fmr1KO mice is reversed following genetic reduction of STEP in a social dominance tube test. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

The percentage of wins by STEPWT/Fmr1KO (n = 10), STEPHT/Fmr1KO (n = 8), and STEPKO/Fmr1KO (n = 6) against STEPWT/Fmr1WT mice is presented. Each mouse was tested against three STEPWT/Fmr1WT mice. Genetically reducing STEP in Fmr1KO mice increases the number of wins against STEPWT/Fmr1WT, indicating that social anxiety in this task is corrected. Data represent the mean percentage of wins (*indicates significantly different from STEPWT/Fmr1WT).

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
2.
Figure 2

Figure 2. Generation of Fmr1KO mice with a selective reduction in STEP. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) Breeding strategy employed in the study. Fmr1KO mice were cross-bred with STEPKO mice on a pure c57Bl/6 background to produce breeder progeny that were STEPHT/Fmr1HT (females) and STEPHT/Fmr1KO (males). Breeders from different litters were then mated to produce offspring with a selective reduction or elimination of STEP and Fmr1. The six offspring analyzed in this study are listed. (b) Representative gels of PCR reactions screening for the presence or absence of the WT and KO (neomycin) STEP and Fmr1 alleles.

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
3.
Figure 8

Figure 8. Effects of STEP and Fmr1 on light/dark box exploration. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

Main effect analysis reveals that Fmr1KO mice spent more time (a) and travel greater distance (b) than Fmr1WT mice in the illuminated side of the light/dark box (a, **P = 0.002; b, **P = 0.014), suggesting decreased anxiety. While the time (a) and distance traveled (b) for STEPHT/Fmr1KO mice tends to be less than STEPWT/Fmr1KO mice, these results did not reach statistical significance (a, P = 0.061; b, P = 0.072. (c) A significant main effect of STEP is observed for the total number of light/dark side entries (*P = 0.004). Specifically, STEPHT and STEPKO mice have fewer total entries than STEPWT mice, providing further support that reducing STEP increases anxiety. Data represent the mean for each measure ± s.e.m. [STEPWT/Fmr1WT (n = 8), STEPHT/Fmr1WT (n = 10), STEPKO/Fmr1WT (n = 7), STEPWT/Fmr1KO (n = 11), STEPHT/Fmr1KO (n = 10), and STEPKO/Fmr1KO (n = 9)].

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
4.
Figure 4

Figure 4. Abnormalities in social approach are reversed in Fmr1KO mice following genetic reduction of STEP. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) Schematic of apparatus during the socialization phase of the social choice task. No significant differences among genotypes are detected in total distance traveled (b) or time in close proximity to the stranger mouse (c). (d) Main effect analysis reveals that Fmr1KO mice enter the area in close proximity to the stranger mouse more times than Fmr1WT (**P = 0.001). STEPHT/Fmr1KO mice have significantly fewer visits than STEPWT/Fmr1KO mice (#P = 0.008), indicating that decreasing STEP levels reverses this phenotype. (e) A significant main effect of STEP genotype was observed for the duration of each entry in close proximity to the stranger mouse (*P = 0.016). Specifically, STEPHT and STEPKO mice spend more time per visit in close proximity to the stranger mouse than STEPWT mice. Data represent the mean for each measure ± s.e.m. [STEPWT/Fmr1WT (n = 8), STEPHT/Fmr1WT (n = 11), STEPKO/Fmr1WT (n = 6), STEPWT/Fmr1KO (n = 13), STEPHT/Fmr1KO (n = 8), and STEPKO/Fmr1KO (n = 6)].

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
5.
Figure 1

Figure 1. Translation of STEP is dysregulated in the absence of FMRP. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) Characterization of synaptoneurosome (SN) and cytosolic (Cyto) fractions. Representative blots with equal amounts of protein demonstrating that PSD-95 is expressed almost exclusively in SNs, and, while expressed in both fractions, STEP is enriched in SNs. (b) GAPDH levels do not vary with Fmr1 genotype or change in response to DHPG stimulation, so these values were used to normalize other protein signals. (c) Main effect analysis reveals that STEP expression is significantly higher in SNs from STEPWT/Fmr1KO mice (*P = 0.038). DHPG treatment significantly increases STEP levels in SNs from STEPWT/Fmr1WT mice (#P = 0.048); however this is completely abolished in STEPWT/Fmr1KO SNs. (d) Expression of STEP in unstimulated Cyto fractions does not differ with Fmr1 genotype, suggesting that the basal increase in STEP expression occurs selectively in SNs. (e) Main effect analysis reveals that PSD-95 expression is significantly higher in SNs from STEPWT/Fmr1KO mice (*P = 0.002). DHPG tends to increase PSD-95 levels in STEPWT/Fmr1WT SNs, but this was not statistically significant (P = 0.089). No DHPG-induced change in PSD-95 expression is observed in STEPWT/Fmr1KO SNs. Data represent the mean normalized protein signal divided by the normalized GAPDH signal ± s.e.m. for all values (n = 3).

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
6.
Figure 5

Figure 5. Genetically decreasing STEP levels ameliorates social novelty-induced hyperactivity in Fmr1KO mice. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) Schematic of apparatus during the social novelty phase of the social choice task. (a) Main effect analysis reveals that Fmr1KO mice travel significantly greater distance than Fmr1WT mice during the social novelty phase (**P = 0.012). In contrast, STEPHT and STEPKO mice travel significantly less distance compared to STEPWT mice (*P = 0.005). The net result is that genetically reducing STEP ameliorates the effect of Fmr1 genotype on locomotion. Significant main effects of Fmr1 are observed for both the total time (c) and number of entries (d) in close proximity to the novel mouse (c, **P = 0.030; d, **P = 0.038), which may be explained, in part, by the overall increased locomotion in Fmr1KO mice (b). (e) No significant differences among genotypes are detected in the duration of each visit in close proximity to the novel mouse. Data represent the mean for each measure ± s.e.m. [STEPWT/Fmr1WT (n = 8), STEPHT/Fmr1WT (n = 11), STEPKO/Fmr1WT (n = 6), STEPWT/Fmr1KO (n = 13), STEPHT/Fmr1KO (n = 8), and STEPKO/Fmr1KO (n = 6)].

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
7.
Figure 7

Figure 7. Genetically reducing STEP in Fmr1KO mice reverses open arm exploration in the elevated plus maze. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) Main effect analysis reveals that Fmr1KO mice enter the open arms more times than Fmr1WT mice (**P = 0.034), indicative of decreased anxiety. In contrast, STEPKO mice enter the open arms significantly less than STEPWT or STEPHT mice (*P = 0.035), suggesting increased anxiety. The net result is that genetically reducing STEP normalizes the effect of Fmr1 genotype on open arm exploration. (b) No significant differences among genotypes are detected in the number of total arm entries, indicating similar locomotion in this task. Significant main effects of Fmr1 are found for the percentage of total time in the center square (c), duration of each center square entry (d), and number of head dips in the open arms (e) (c, **P = 0.008; d, **P = 0.009; e, **P = 0.011), suggesting that Fmr1KO mice have increased exploratory behaviors compared to Fmr1WT mice. In these measures (c–e), there were no main effects of STEP genotype. Data represent the mean for each measure ± s.e.m. [STEPWT/Fmr1WT (n = 10), STEPHT/Fmr1WT (n = 11), STEPKO/Fmr1WT (n = 10), STEPWT/Fmr1KO (n = 13), STEPHT/Fmr1KO (n = 8), and STEPKO/Fmr1KO (n = 7)].

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.
8.
Figure 3

Figure 3. Genetically reducing STEP decreases audiogenic seizures (AGS) and reduces seizure-induced c-Fos activation in the periaqueductal gray (PAG) of Fmr1KO mice. From: Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

(a) None of the STEPWT/Fmr1WT (n = 12), STEPHT/Fmr1WT (n = 13), or STEPKO/Fmr1WT (n = 5) mice show seizure activity in response to a 130 dB stimulus. On the contrary, 76% of STEPWT/Fmr1KO (n = 21) exhibit a response. Genetically reducing STEP decreases AGS since only 53.3% of STEPHT/Fmr1KO (n = 30) and 43.5% of STEPKO/Fmr1KO (n = 23) mice have a response (*indicates significantly different from STEPWT/Fmr1WT, #indicates significantly different from STEPWT/Fmr1KO). Data represent the mean percentage of mice showing seizure incidence (wild running, tonic/clonic seizure). (b–g) Comparison of c-Fos immunoreactivity in the PAG among different genotypes and seizure responses 30 min after exposure to the audio stimulus. Scale equals 200 microns in (b–d) and 10 microns in (e–f). (b, e) Only a sparse number of c-Fos+ neurons are found in the PAG of STEPWT/Fmr1WT mice when no seizure response is observed. (c, f) STEPWT/Fmr1KO mice that have seizures show robust c-Fos staining in the PAG. (d, g) The number of seizure-induced c-Fos+ neurons is consistently less in STEPKO/Fmr1KO mice compared to STEPWT/Fmr1KO mice. (h) Number of c-Fos+ cells in the PAG among genotypes in the absence or presence of a seizure. When no response is observed, there are no significant differences between STEPWT/Fmr1WT (n = 5), STEPWT/Fmr1KO (n = 4), or STEPKO/Fmr1KO (n = 6) mice. Following seizures, the number of c-Fos+ PAG neurons is significantly increased regardless of genotype (*P = 0.0001); however this number is significantly less in STEPKO/Fmr1KO (n = 6) compared to STEPWT/Fmr1KO (n = 5) mice (#P ≤ 0.01). Data represent the mean c-Fos+ cells in the PAG ± s.e.m.

Susan M. Goebel-Goody, et al. Genes Brain Behav. ;11(5):586-600.

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