Further Behavioral Characterization of An Inbred Mouse Model of Restricted, Repetitive Behavior

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
11:00 AM
A. M. Muehlmann, A. Mihalik, D. Koppuzha and M. H. Lewis, University of Florida, Gainesville, FL
Background:  Although autism spectrum disorder (ASD) is a highly heritable complex genetic disorder, clinical and animal studies have provided only very limited findings with respect to the genes controlling restricted, repetitive behavior (RRB). It appears, however, that RRB is likely influenced by genes that are largely independent of those that influence the social or communication deficits. Moreover, RRB appears to be familial and several candidate genes have been advanced (e.g., GABRB3, SLC6A4, SLC25A12). Animal models with the requisite validity could aid substantially in identifying genomic factors associated with RRB. Thus, in order to investigate the genetics of RRB, we have further characterized the expression of the restricted, repetitive behavioral phenotype reported in the C58/J inbred mouse strain (Moy et al., 2008; Ryan et al, 2009). Careful, quantitative characterization of the behavioral phenotype is critical for subsequent genotype-phenotype correlations.

Objectives:  1) to assess both repetitive motor behaviors (“lower order” RRB) as well as to assess restricted behaviors and resistance to change (“higher order” RRB) in C58 mice. 2) to compare the behavior of C58 mice on these measures to C57BL/6 mice, a genetically closely related strain that does not appear to exhibit appreciable levels of motor stereotypy; 3) to assess repetitive motor behavior in the offspring of the C58XC57BL/6 F1 intercross.

Methods:  We assessed repetitive motor behavior across the 12 hour dark cycle using automated apparatus and video-recording. We used a holeboard exploration task to assess restricted behavior, a reversal learning water T-maze task to assess resistance to change, and the marble-burying task to assess perseverative motor responding.

Results:  C58 mice displayed high levels of spontaneous repetitive motor behavior, averaging 7,951 stereotyped responses (range of 2,918 to 14,679) for the 12 hour dark cycle whereas the C57BL/6 strain averaged only 29 responses (0 to 296) over the same period.  These responses consisted of repetitive vertical jumping and backward somersaulting. No significant strain differences were noted in the holeboard exploration task. C58 mice engaged in less marble-burying than C57BL/6 mice and marble-burying was significantly inversely correlated with stereotyped motor behavior. C58 mice proved to have great difficulty in the T-maze task used to assess resistance to change precluding valid strain comparisons. Finally, the F1 C58XC57BL/6 intercross mice displayed an intermediate repetitive motor behavior phenotype compared to the parental strains with clear evidence of a sex effect with females showing higher levels of stereotyped motor behavior.

Conclusions:  This study provides the first quantitative assessment of the spontaneous repetitive motor behavior of C58 mice and comparison to a genetically similar control strain. These findings confirm stereotypy as a robust, quantifiable, and reliable behavioral phenotype in this strain. Other measures of “higher order” repetitive behavior did not yield reliable strain differences. The F1 intercross findings support the genetic basis of repetitive behavior and provide further support for the C58 inbred strain as a useful animal model to investigate the genetic basis of repetitive motor behavior. Such studies should have important translational value in ascertaining the genetics of RRB in ASD.

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