Mecp2 truncation in male mice promotes affiliative social behavior

Abstract

Mouse models of Rett syndrome, with targeted mutations in the Mecp2 gene, show a high degree of phenotypic consistency with the clinical syndrome. In addition to severe and age-specific regression in motor and cognitive abilities, a variety of studies have demonstrated that Mecp2 mutant mice display impaired social behavior. Conversely, other studies indicate complex enhancements of social behavior in Mecp2 mutant mice. Since social behavior is a complicated accumulation of constructs, we performed a series of classic and refined social behavior tasks and revealed a relatively consistent pattern of enhanced pro-social behavior in hypomorphic Mecp2 (308/Y) mutant mice. Analyses of repetitive motor acts, and cognitive stereotypy did not reveal any profound differences due to genotype. Taken together, these results suggest that the mutations associated with Rett syndrome are not necessarily associated with autism-relevant social impairment in mice. However, this gene may be a valuable candidate for revealing basic mechanisms of affiliative behavior.

Figure 1. Mecp2 mutant mice show increased affiliation in the VBS

(a) and (b) display the frequencies of each of the eight behaviors scored during 24 scans across the first four hours of three consecutive dark phases and (c) and (d) display the same behaviors across three consecutive light phases. Horizontal lines indicate a significant main effect of Day, and vertical lines indicate a significant Genotype main effect. y/+ denotes wild-type and y/− are hemizygous mutant mice. * p<0.05; ** p<0.01, *** p<0.0001. Symbols above individual means indicate a significant post-hoc effect: # p<0.05; $ p<0.001. Wild-type (y/+) N=9, mutant (y/−) N=6.

Figure 2. Three-Chamber Sociability in Mecp2 mutant (y/−) and wild-type (y/+) littermates

Both wild-type (y/+) and mutant mice (y/−) display increased duration of time in the chamber containing an unfamiliar mouse compared to an empty cup (a). Wild type and mutant mice did not differ in the number of entries into the outer compartments of the sociability phase of the three chamber task (b). Frequency (c) and duration (d) of behaviors in each of the two outer stimulus compartments indicate that mutant mice have lower durations of contact with the cup in either chamber. Horizontal lines above columns indicate significant main effects for Genotype or Stimulus. Asterisks (*) indicate significant Genotype main effects. Stimulus main effects are denoted by an ampersand (&). * p<0.05, *** p<0.001, & p<0.001. Post hoc tests: # p<0.05. N=9/group.

Figure 3. Slight alterations in patterns of autogrooming in Mecp2 mutant mice

Frequency (a) and duration (b) of body site-specific patterns of grooming. MeCp2 mutant mice (y/−) show increased frequency of tail/genital grooming and an increased duration of paw licking compared to wild-type littermate controls (y/+). No significant differences were found in syntactical parameters of grooming (c). *p<0.05; **p<0.01. N=9/group.

Figure 4. Repetitive novel object contact task

Wild-type and mutant Mecp2 mice show similar spontaneous investigation of novel toys (a,b). Similarly, wild-type (y/+) and mutant Mecp2 mice (y/−) show no differences in the number of sequenced visits to the unfamiliar objects (c). N=9/group.

Figure 5. Patterns of social interaction in the social proximity task

Mecp2 mutant mice (y/−) show increased frequency of crawl under (a). Additionally, they show higher duration of nose-to-face interactions, as well as increased durations of crawl over and crawl under behavior (b) compared to wild-type littermates (y/+). *p<0.05; **p<0.01. N=9/group.

Figure 6. Elevated scent marking in a nonsocial and social context in Mecp2 mutant mice

Mutant mice (y/−) scent mark more to an empty chamber and when an unfamiliar adult CD-1 is behind a divider compared to wild-type littermates (y/+). Wild-type (y/+) N=9, mutant (y/−) N=8. Genotype main effect * p<0.05.

Figure 7. Comparison of behavior in the resident-intruder task

Mecp2 mutant mice (y/+) show similar frequencies of behavior to an unfamiliar intruder compared to their wild-type littermates (y/+) (a). Mutant mice show decrease duration of following behavior (b). *p<0.05. Wild-type (y/+) N=9, mutant (y/−) N=8.