Objectives: 1) Extend studies of SERT Ala56 knock-in mice into a second inbred strain, C57BL/6, to evaluate penetrance of observed phenotypes across genetic backgrounds; 2) Evaluate behavioral rigidity in SERT Ala56 mice on a probabilistic reversal learning task that models the behavioral trait of insistence on sameness.3) Assess the development of the somatosensory system in SERT Ala56 mice.
Methods: SERT Ala56 mice on a 129S genetic background were crossed 10 generations to C57BL/6 mice. Genetic markers were used to establish 99% congenic status. Separately, the native 129S6 SERT was crossed 10 generations to C57BL/6 to establish appropriate control for strain-dependent variation in the SERT gene. Measures of social, communication, and repetitive behavior were used to assess penetrance of observed phenotypes. Sensitivity to serotonin receptor agonists was also measured to assess impact of this variant on brain 5-HT homeostasis in the C57BL/6 background. Finally, assessment of probabilistic reversal learning and sensory development are underway.
Results: Variable penetrance of the SERT Ala56 variant was seen for different phenotypes across inbred strains. Consistent with previous findings in the 129S mice, SERT Ala56 mice on the C57BL/6 background were more likely to back out on the tube test for dominance when confronted with a control animal (P < 0.01). In contrast to the 129S background, no difference between genotypes was observed on the three-chamber sociability test or in hanging behavior in the home cage. At postnatal day 7, C57BL/6 SERT Ala56 pups showed increased vocalizations when separated from the dam (P < 0.05), which is opposite to the phenotype observed in the 129S background. Sensitivity to serotonin 5-HT1A and 5-HT2A receptor agonists was not significantly different between SERT Ala56 mice and controls on the C57BL/6 background. Results from objectives 2 and 3 will also be presented.
Conclusions: Variable penetrance of SERT Ala56 phenotypes across genetic backgrounds is consistent with observations in families segregating this variant, where some but not all individuals with the variant share a diagnosis of autism. These results also parallel findings in other genetic mouse models of autism, including the Fmr1 knockout mouse, which shows variable penetrance of behavioral phenotypes across inbred strains. Genetic differences between 129S and C57BL/6 inbred strains may include gene variants that modify sensitivity of the 5-HT system to SERT variation. Other manipulations of the 5-HT system impact probabilistic reversal learning and development of the somatosensory system in mice, but increased SERT function has not previously been examined.