Absence of preference for social novelty and increased grooming in integrin β3 knockout mice: initial studies and future directions

Abstract

Elevated whole blood serotonin 5-HT, or hyperserotonemia, is a common biomarker in autism spectrum disorder (ASD). The integrin β3 receptor subunit gene (ITGB3) is a quantitative trait locus for whole blood 5-HT levels. Recent work shows that integrin β3 interacts with the serotonin transporter (SERT) in both platelets and in the midbrain. Furthermore, multiple studies have now reported gene-gene interaction between the integrin β3 and SERT genes in association with ASD. Given the lack of previous data on the impact of integrin β3 on brain or behavioral phenotypes, we sought to compare mice with decreased or absent expression of the integrin β3 receptor subunit (Itgb3 +/- and -/-) with wildtype littermate controls in behavioral tasks relevant to ASD. These mice did not show deficits in activity level in the open field or anxiety-like behavior on the elevated plus maze, two potential confounds in the evaluation of mouse social behavior. In the three-chamber social test, mice lacking integrin β3 were shown to have normal sociability but did not show a preference for social novelty. Importantly, the absence of integrin β3 did not impair olfaction or the ability to recall familiar social odors. Additionally, mice lacking integrin β3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin β3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms.

Figure 1. Open Field Activity

Mean and standard error of the mean are shown by genotype (13 +/+, 23 +/-, 8 -/-) for cumulative data over 15 minutes spent in the activity chamber for each genotype. A: Distance traveled in cm. B: Time spent in ambulatory movement. C: Time spent not moving. D: Time spent in the vertical position. No significant genotype effects were detected by one-way ANOVA on any of the measures of activity.

Figure 2. Elevated Plus Maze

Mean and standard error of the mean are shown by genotype (13 +/+, 23 +/-, 8 -/-) for cumulative data over 5 minutes spent in the elevated plus maze. A: Ratio of time spent in the open arms divided by the time spent in either the open or closed arms. B: Total entries into the open arms. C: Total entries into either open or closed arms. No significant genotype effects were detected by one-way ANOVA on any measure.

Figure 3. Social and Olfactory Behavior

A and B: Three-chamber social test. Mean and standard error of the mean are shown by genotype (10 +/+, 20 +/-, 6 -/-) for the cumulative data over each 10-minute test session. A: Time spent within 1 cm (‘sniffing’) of the wire cage containing the novel mouse or the novel object (empty wire cage). B: Time spent within 1 cm of the wire cage containing the familiar mouse or the novel mouse. C: Olfactory Habituation-Dishabituation. Mean and standard error of the mean are shown by genotype (11 +/+, 8 -/-) for the time spent within 2 cm of the cotton swab containing the odor stimulus over each 2-minute odor presentation.

Figure 4. Grooming behavior

A: Grooming behavior in the novel environment. Mean and standard error of the mean are shown by genotype (6 +/+, 6 +/-, 7 -/-) for seconds spent grooming in a novel cage scored by stopwatch over a 10 minute observation period. B: Grooming behavior in the home cage. Mean and standard error of the mean are shown by genotype (6 +/+, 3 +/-, 4 -/-) for seconds spent grooming in the home cage as scored by the automated HomeCageScan software (Clever Sys, Inc., Reston, VA).