Consistent hypersocial behavior in mice carrying a deletion of Gtf2i but no evidence of hyposocial behavior with Gtf2i duplication: Implications for Williams-Beuren syndrome and autism spectrum disorder.

Introduction: Williams-Beuren syndrome (WBS) is a developmental disorder caused by hemizygous deletion of human chromosome 7q11.23. Hypersocial behavior is one symptom of WBS and contrasts with hyposociality observed in autism spectrum disorder (ASD). Interestingly, duplications of 7q11.23 have been associated with ASD. The social phenotype of WBS has been linked to GTF2I or general transcription factor IIi (TFII-I). Duplication of GTF2I has also been associated with ASD. Methods: We compared mice having either a deletion (Gtf2i+/- ) or duplication (Gtf2i+/dup ) of Gtf2i to wild-type (Gtf2i+/+ ) littermate controls in a series of behavioral tasks including open-field activity monitoring, olfactory probes, a social choice task, social transmission of food preference, habituation-dishabituation, and operant social motivation paradigms. Results: In open-field observations, Gtf2i+/- and Gtf2i+/dup mice demonstrated normal activity and thigmotaxis, and surprisingly, each strain showed a significant preference for a stimulus mouse that was not observed in Gtf2i+/+ siblings. Both Gtf2i+/- and Gtf2i+/dup mice demonstrated normal olfaction in buried food probes, but the Gtf2i+/- mice spent significantly more time investigating urine scent versus water, which was not observed in the other strains. Gtf2i+/- mice also spent significantly more time in nose-to-nose contact compared to Gtf2i+/+ siblings during the open-field encounter of the social transmission of food preference task. In operant tasks of social motivation, Gtf2i+/- mice made significantly more presses for social rewards than Gtf2i+/+ siblings, while there was no difference in presses for the Gtf2i+/dup mice. Discussion: Results were remarkably consistent across testing paradigms supporting a role for GTF2i in the hypersocial phenotype of WBS and more broadly in the regulation of social behavior. Support was not observed for the role of GTF2i in ASD.

Quantifying Social Motivation in Mice Using Operant Conditioning.

In this protocol, social motivation is measured in mice through a pair of operant conditioning paradigms. To conduct the experiments, two-chambered shuttle boxes were equipped with two operant levers (left and right) and a food receptacle in one chamber, which was then divided from the second chamber by an automated guillotine door covered by a wire grid. Different stimulus mice, rotated across testing days, served as a social stimulus behind the wire grid, and were only visible following the opening of the guillotine door. Test mice were trained to lever press in order to open the door and gain access to the stimulus partner for 15 sec. The number of lever presses required to obtain the social reward progressively increased on a fixed schedule of 3. Testing sessions ended after test mice stopped lever pressing for 5 consecutive minutes. The last reinforced ratio or breakpoint can be used as a quantitative measure of social motivation. For the second paradigm, test mice were trained to discriminate between left and right lever presses in order to obtain either a food reward or the social reward. Mice were rewarded for every 3 presses of each respective lever. The number of food and social rewards can be compared as a measurement of the value placed upon each reward. The ratio of each reward type can also be compared between mouse strains and the change in this ratio can be monitored within testing sessions to measure satiation with a given reward type. Both of these operant conditioning paradigms are highly useful for the quantification of social motivation in mouse models of autism and other disorders of social behavior.