Behavioral and Neurochemical Characterization of the Serotonin Transporter Gly56Ala Knock-in Mouse

Background: Elevated platelet serotonin (5-HT), termed hyperserotonemia, is present in about one-quarter of children with autism. Linkage studies in families containing two or more male children with autism have implicated the chromosome 17q11.2 region containing the serotonin transporter gene (SERT, SLC6A4). Common functional variants in SERT fail to explain the strong linkage signal observed at this locus. In families with male-only probands, rare SERT amino acid variants show an association with autism. The most common of these variants, Gly56Ala, is associated with rigid-compulsive behaviors and sensory aversion. Objectives: In vitro studies (Prasad et al., 2005; Prasad et al., 2009) demonstrated that the 56Ala variant (1) displays increased basal 5-HT transport, (2) exhibits elevated basal phosphorylation, and (3) is refractory to regulation through PKG and p38 MAPK pathways. To pursue the physiological significance of these findings in vivo, we developed a SERT Gly56Ala knock-in mouse line. Methods: Serotonin levels were measured in whole blood and in brain by high-performance liquid chromatography. Serotonin uptake was measured in platelets and midbrain synaptosomes. Mouse behavior was assessed using standard techniques to measure activity level, anxiety-like behavior, social behavior, and acoustic startle / prepulse inhibition. Results: SERT 56Ala variant mice exhibit elevated whole blood 5-HT. Initial behavioral studies suggest social and sensory alterations in the SERT 56Ala variant mice. Conclusions: The SERT 56Ala mouse is the first mouse model targeting an autism-associated gene to manifest hyperserotonemia. Initial studies provide preliminary support for altered behavioral traits with face validity for autism spectrum disorder. Ongoing efforts seek to connect the intermediate steps between the SERT 56Ala variant and the observed neurochemical and behavioral phenotype.