BTBR T⁺ Itpr3^tf/J (BTBR) mice, a suitable animal model to study anxiety and repetitive behavior in Autism Spectrum Disorders (ASD)

In her FFG-funded PhD thesis at Scantox in cooperation with Prof. Marcello Leopoldo from the University of Bari, Italy, Shirin Sharghi behaviorally characterized the BTBR T⁺ Itpr3^tf/J mouse model of Autism Spectrum Disorders (ASD). BTBR T⁺ Itpr3^tf/J mice were allocated to three different treatment groups of either LP-211 (a serotonergic compound), R-Baclofen (a GABAergic drug) or vehicle.

Already at the age of 6 weeks, vehicle-treated BTBR mice showed significantly higher thigmotaxis, rearing numbers and duration as well as time spent in the center of the Open Field box during the whole 30 minutes of testing when compared to C57BL/6JRj animals (Figure 1). These data indicate higher anxiety and compromised non-selective attention/fear-like behavior in BTBR animals. LP-211 and R-Baclofen treatment did not significantly affect those parameters.

In the Elevated Plus Maze test a higher velocity and an increased number of entries to the closed arms suggest a higher anxiety and stress-related behavior in vehicle-treated BTBR mice compared to C57BL/6JRj animals at the age of 10 weeks (Figure 2). The increased frequency of entering the central zone could further indicate repetitive behavior in BTBR mice. LP-211 treatment was able to slightly ameliorate these effects.

To validate repetitive behavior, vehicle-treated BTBR animals were tested for grooming behavior at the age of 10 weeks. Analysis revealed a significantly higher grooming duration compared to C57BL/6JRj mice. A trend towards a reduced grooming duration was observed after LP-211 and R-Baclofen treatment. However, the number of grooming events was similar between all groups (Figure 3).

In conclusion, Shirin was able to show that BTBR T⁺ Itpr3^tf/J mice present higher anxiety and repetitive behavior compared to C57BL/6JRj mice, while a single injection of LP-211 and R-Baclofen in the here applied concentration were barely able to ameliorate this phenotype. These findings suggest that BTBR mice are a suitable model to study typical ASD symptoms.

Figure 1: Open Field Test. Thigmotaxis (A), rearing numbers (B), rearing duration (C), time spent in the center (D). Animals were recorded for 30 minutes and evaluated in 5-minutes intervals. Mean ± SEM. Two-way ANOVA followed by Bonferroni’s post hoc test all versus B; *p<0.05, **p<0.01, ***p<0.001.

Figure 2: Elevated Plus Maze Test. Velocity (A), number of entries in closed arms (B), number of entries to central zone (C). Mean + SEM. One-way ANOVA followed by Kruskal-Wallis (A) and Bonferroni’s (B and C) post hoc test; all versus B; *p<0.01.

Figure 3: Grooming Test. Duration of grooming (A), grooming episodes (B). Mean + SEM. One-way ANOVA followed by Kruskal-Wallis post hoc test; all versus B; ***p<0.001.

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