GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism - PubMed (original) (raw)

Marjelo A Mines et al. PLoS One. 2010.

Abstract

Background: Nearly 1% of children in the United States exhibit autism spectrum disorders, but causes and treatments remain to be identified. Mice with deletion of the fragile X mental retardation 1 (Fmr1) gene are used to model autism because loss of Fmr1 gene function causes Fragile X Syndrome (FXS) and many people with FXS exhibit autistic-like behaviors. Glycogen synthase kinase-3 (GSK3) is hyperactive in brains of Fmr1 knockout mice, and inhibition of GSK3 by lithium administration ameliorates some behavioral impairment in these mice. We extended our studies of this association by testing whether GSK3 contributes to socialization behaviors. This used two mouse models with disrupted regulation of GSK3, Fmr1 knockout mice and GSK3 knockin mice, in which inhibitory serines of the two isoforms of GSK3, GSK3alpha and GSK3beta, are mutated to alanines, leaving GSK3 fully active.

Methodology/principal findings: To assess sociability, test mice were introduced to a restrained stimulus mouse (S1) for 10 min, followed by introduction of a second restrained stimulus mouse (S2) for 10 min, which assesses social preference. Fmr1 knockout and GSK3 knockin mice displayed no deficit in sociability with the S1 mouse, but unlike wild-type mice neither demonstrated social preference for the novel S2 mouse. Fmr1 knockout mice displayed more anxiety-related behaviors during social interaction (grooming, rearing, and digging) than wild-type mice, which was ameliorated by inhibition of GSK3 with chronic lithium treatment.

Conclusions/significance: These results indicate that impaired inhibitory regulation of GSK3 in Fmr1 knockout mice may contribute to some socialization deficits and that lithium treatment can ameliorate certain socialization impairments. As discussed in the present work, these results suggest a role for GSK3 in social behaviors and implicate inhibition of GSK3 as a potential therapeutic.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Influences of lithium treatment on the sociability of Fmr1 knockout and wild-type mice.

A. Diagram of the social interaction apparatus. The ovals represent the wire enclosures used to secure the stimulus mice, S1 in Chamber 1 and S2 in Chamber 3. The breaks in the center walls represent the circular openings allowing the mice to move between chambers. B. Representative image of genotyping results from wild-type and Fmr1 knockout mice (top). Chronic lithium treatment increased inhibitory serine-phosphorylation of GSK3 (PS-GSK3) on serine-21 of GSK3α and on serine-9 of GSK3β in the hippocampus of wild-type and Fmr1 knockout mice (bottom) as reported previously , . C. Mean total time spent by wild-type mice in each chamber during the sociability period. Wild-type (WT) (n = 9) mice spent significantly more time in Chamber 1, the chamber with S1, compared to empty Chamber 2 or Chamber 3 with the wire enclosure only. Chronic lithium treatment of WT mice (n = 5) had no significant effect on sociability. * p<0.05 comparing time spent in Chamber 1 with time in Chambers 2 and 3. D. Mean total time spent by Fmr1 knockout mice in each chamber during the sociability period. Fmr1 knockout (FX) mice (n = 9) spent significantly more time in Chamber 1, the chamber with S1, compared to empty Chamber 2 or Chamber 3 with the wire enclosure only. FX mice (n = 6) chronically treated with lithium displayed a significant increase in time spent in Chamber 1, with S1, as compared to time in Chambers 2 or 3. Treated mice also displayed a significant increase in time spent in Chamber 1 and a significant decrease in time spent in Chamber 3, as compared to untreated controls. * p<0.05 comparing time spent in Chamber 1 with Chambers 2 and 3; # p<0.05 compared to untreated FX mice. E. The total number of nose contacts by the test mouse with S1 was equivalent for untreated WT and FX mice. Chronic lithium treatment significantly increased the number of nose contacts for both WT and FX mice. * p<0.05 compared to untreated group mates. F. The duration of nose contacts with S1 was lower in FX than WT mice. Lithium treatment had no effect on social interaction (defined as the average duration of nose contacts). * p<0.05 compared to untreated WT mice.

Figure 2

Figure 2. Fmr1 knockout mice exhibit impairments in social preference.

A. Mean total time spent by wild-type mice in each chamber during the social preference period. Wild-type (WT) mice (n = 9) spent significantly more time in Chamber 3 with the novel S2 mouse compared to empty Chamber 2, or to Chamber 1 with the familiar S1 mouse. Chronic lithium treatment did not significantly alter time spent in each chamber (n = 5). * p<0.05 comparing time spent in Chamber 3 with Chambers 1 and 2. B. Mean total time spent by Fmr1 knockout mice in each chamber during the social preference period. There was not a significant difference in the amount of time Fmr1 knockout (FX) mice (n = 9) spent in Chamber 3 with the novel mouse S2 and in Chamber 1 with the familiar mouse S1. Chronic lithium treatment did not significantly alter time spent in each chamber (n = 6). C. WT mice, but not FX mice, displayed a significant preference for nose contacts with S2, compared to S1. Chronic lithium treatment significantly increased the number of nose contacts with S2 by both WT and FX mice. * p<0.05 nose contacts with S2 compared with S1; ** p<0.05 compared to nose contacts with S2 by untreated group mates. D. The duration of nose contacts with S1 and S2 was not significantly different between WT and FX mice. Chronic lithium treatment had no significant effect on nose contact duration.

Figure 3

Figure 3. Fmr1 knockout mice exhibit increased social anxiety-related behaviors during social interaction.

A. During the sociability period, there was not a significant difference in grooming times of Fmr1 knockout (FX) mice and wild-type (WT) mice. Chronic lithium treatment had no significant effect on WT grooming times but slightly decreased the percentage of FX mice with grooming times above the median time. Dashed lines represent median grooming times, 12 sec and 12.5 sec for WT and FX mice, respectively. B. FX mice spent significantly more time rearing and digging than WT mice during the sociability period. Chronic lithium treatment significantly decreased duration of rearing and digging behaviors in both groups of mice. *p<0.05 compared to untreated group mates; ** p<0.05 comparing untreated WT and FX mice. C. During the social preference period, there was not a significant difference in grooming times of Fmr1 knockout (FX) mice and wild-type (WT) mice. Chronic lithium treatment had no significant effect on grooming times, but slightly decreased the percentage of WT and FX mice with grooming times above the median time. Dashed lines represent median grooming times, 8.5 sec and 11 sec for WT and FX mice, respectively. D. FX mice spent significantly more time rearing and digging than WT mice during the social preference period. Chronic lithium treatment significantly decreased duration of rearing and digging behaviors in both groups of mice. * p<0.05 compared to untreated group mates; ** p<0.05 comparing untreated WT and FX mice.

Figure 4

Figure 4. Sociability is not altered in GSK3 knockin mice.

A. GSK3 knockin mice lack serine-phosphorylation of GSK3 (PS-GSK3) on serine-21 of GSK3α and on serine-9 of GSK3β, which is evident in wild-type mice, as reported previously , . Total GSK3 levels are equivalent in GSK3 knockin mice and wild-type mice. B. Mean total time spent in each chamber during the sociability period. Wild-type (WT) (n = 7) mice and GSK3 knockin (KI) (n = 10) mice spent significantly more time in Chamber 1, the chamber with S1, compared to empty Chamber 2 or Chamber 3 with the wire enclosure only. * p<0.05 comparing time spent in Chamber 1 with Chambers 2 and 3. C. Social approach, the total number of nose contacts by the test mouse with S1, was equivalent for untreated WT and KI mice. D. There was no difference in social interaction between WT and KI mice.

Figure 5

Figure 5. GSK3 knockin mice exhibit impairments in social preference.

A. Mean total time spent in each chamber during the social preference period. Wild-type (WT) mice (n = 11), but not GSK3 knockin (KI) mice (n = 10), spent significantly more time in Chamber 3 with the novel S2 mouse compared to empty Chamber 2, or to Chamber 1 with the familiar (S1) mouse. * p<0.05 comparing time spent in Chamber 3 with Chambers 1 and 2. B. GSK3 KI mice display deficits in social approach preference, as indicated by no significant difference in the number of nose contacts with S1 or S2. C. The duration of nose contacts with S2 was significantly greater than with S1 for WT, but not GSK3 KI, mice. * p<0.05 comparing WT duration of nose contacts with S1 and S2.

Figure 6

Figure 6. Anxiety-related behaviors during social interaction in GSK3 knockin mice.

A. During the sociability period, there was not a significant difference in grooming times of GSK3 knockin (KI) mice and wild-type (WT) mice, but the percentage of wild-type (WT) mice with grooming times above the median was higher than GSK3 knockin (KI) mice. Dashed lines represent median grooming times, 12.5 sec. B. GSK3 KI mice spent significantly less time rearing and digging than WT mice during the sociability period. * p<0.05 compared to untreated WT mice. C. During the social preference period, there was not a significant difference in grooming times of GSK3 knockin (KI) mice and wild-type (WT) mice, but the percentage of KI mice with grooming times above the median was slightly higher than WT controls. Dashed lines represent median grooming times, 12.5 sec. D. WT and GSK3 KI mice spent similar times rearing and digging during the social preference period.

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