Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging

The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, , has been extensively studied. Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an knockout mouse on a C57BL/6 genetic background, along with an Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Individually (same sex, same background, same genotype), the only differences found were in the female knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization.