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. 2008 Mar 5;187(2):207-20.
doi: 10.1016/j.bbr.2007.09.009. Epub 2007 Sep 14.

Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder

Timothy M DeLorey  1 , Peyman Sahbaie, Ezzat Hashemi, Gregg E Homanics, J David Clark
Affiliations

Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder

Timothy M DeLorey et al. Behav Brain Res. .

Abstract

Objective: GABA(A) receptors play an important regulatory role in the developmental events leading to the formation of complex neuronal networks and to the behaviors they govern. The primary aim of this study was to assess whether gabrb3 gene deficient (gabrb3(-/-)) mice exhibit abnormal social behavior, a core deficit associated with autism spectrum disorder.

Methods: Social and exploratory behaviors along with non-selective attention were assessed in gabrb3(-/-), littermates (gabrb3(+/+)) and progenitor strains, C57BL/6J and 129/SvJ. In addition, semi-quantitative assessments of the size of cerebellar vermal lobules were performed on gabrb3(+/+) and gabrb3(-/-) mice.

Results: Relative to controls, gabrb3(-/-) mice exhibited significant deficits in activities related to social behavior including sociability, social novelty and nesting. In addition, gabrb3(-/-) mice also exhibited differences in exploratory behavior compared to controls, as well as reductions in the frequency and duration of rearing episodes, suggested as being an index of non-selective attention. Gabrb3(-/-) mice also displayed significant hypoplasia of the cerebellar vermis compared to gabrb3(+/+) mice.

Conclusions: The observed behavioral deficits, especially regarding social behaviors, strengthens the face validity of the gabrb3 gene deficient mouse as being a model of autism spectrum disorder.

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Figures

Figure 1
Figure 1
Diagram of the automated apparatus used in assessing social behavior in mice. Side view showing location of infra-red photo-sensors and chamber partitions. Partitions can be automatically opened to create a 5 cm wide opening, allowing the test mouse to pass freely from one chamber to the next. A wire mesh wall separates each of the interaction chambers from an adjacent stimulus cage, which will either be empty or contain a “stranger mouse”.
Figure 2
Figure 2
Sociability histograms of the time that mice spent in each of the 3 chambers of the social interaction apparatus. The black bars represent the time spent in interaction chamber #1, adjacent to the stimulus cage containing an unfamiliar mouse (stranger mouse #1), grey bars represent time in the neutral central chamber and white is time in interaction chamber #2, adjacent to an empty stimulus cage. Data presented as the mean ± SEM. C57BL/6J n=6, 129/SvJ n=6, gabrb3+/+ n=6, gabrb3-/- n=6. *p<0.05, **p<0.01.
Figure 3
Figure 3
Social novelty histograms of the mean time (±SEM) mice spent in the interaction chamber adjacent to the now familiar stranger mouse #1 (black bar), the unfamiliar stranger mouse #2 (white bar) or in the neutral central chamber (grey bar). As expected all three control genotypes exhibited a significant preference for the unfamiliar mouse (stranger mouse #2) over the now familiar mouse (stranger mouse #1). The preference for stranger mouse #2 remained significant into the second five min epoch for both C57BL/6J and 129/SvJ mice. C57BL/6J n=6, 129/SvJ n=6, gabrb3+/+ n=6, gabrb3-/- n=6. **p<0.01, ***p<0.001.
Figure 4
Figure 4
Histograms of the sociability and the preference for social novelty assessed from videotape, by an observer, blind to the genotype of the test mice. Observer scores in the sociability test are presented as the total time, during a 10 min test period, that test mice spent with their noses within 2 cm of the wire mesh of the stimulus cage containing an unfamiliar mouse (stranger mouse #1) versus the total time the test mice spent with their noses within 2 cm of the wire mesh of the stimulus cage that was empty. In the preference for social novelty test the data is presented as the amount of time mice were observed to have their noses within 2 cm of the stimulus cage containing stranger mouse #1 (the now familiar mouse) versus the stimulus cage containing stranger mouse #2 (the new unfamiliar mouse). * p<0.05, **p<0.01, ***p<0.001.
Figure 5
Figure 5
Histogram of the percentage of the total 10 min test period that each mouse genotype spent sniffing at the stimulus cage containing A.) Stranger mouse #1 in the sociability test. B.) Stranger mouse #2 in the social novelty test and C.) % of total time spent sniffing at both Stranger mouse #1 and Stranger mouse #2 in the social novelty test. * p<0.05, **p<0.01, ***p<0.001
Figure 6
Figure 6
A.) Histogram of the mean time (±SEM) that each mouse genotypes spent interacting with freshly introduced nesting material (nestlet) during three separate 10 min observations taken over a 1 hr period immediately after the introduction of the nestlet. B.) Histogram of average nest scores (mean ± SEM), taken 48 hr after nestlet introduction. *p<0.05, **p<0.01, ***p<0.001. Gabrb3-/- n=6, gabrb3+/+ n=8, C57BL/6J n=8, 129/SvJ n=8.
Figure 7
Figure 7
Representative examples of the exploratory paths taken by a gabrb3+/+ and gabrb3-/- mouse in an open field chamber that contained a novel object (an empty round cage, depicted as a solid black disc) placed in the center, that was not present during the acclimation phase of the test. The arrow indicates an example of the stereotypical circling often exhibited by gabrb3-/- mice.
Figure 8
Figure 8
A.) Average rearing frequency (mean ± S.E.M.) demonstrated by each genotype, when placed in an open field chamber containing a novel object. Post hoc analysis revealed a significant difference (p<0.001) between gabrb3-/- mice and each control genotype in rearing frequency over the entire 10 min test period. B.) Average duration of a rearing event for each mouse genotype, averaged over the entire 10 min testing period in a novel environment. Gabrb3-/- n=7, gabrb3+/+ n=7, C57BL/6J n=8, 129/SvJ n=7. *p<0.05, ***p<0.001
Figure 9
Figure 9
Representative examples of toluidine blue stained midsagittal sections through the cerebellar vermis (0.36-0.60 mm lateral from the midsagittal line) from gabrb3+/+ and gabrb3-/- mice. A roman numeral identifies each cerebellar vermal lobule. Lobules VI-VII on the gabrb3+/+ brain section have been outlined using a white dashed line to indicate the area being measured and compared.
Figure 10
Figure 10
Histogram of the measured surface area of cerebellar vermal lobules in gabrb3+/+ (n=4) and gabrb3-/- (n=5) mice. *p<0.05, **p<0.01.
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