An autism-associated serotonin transporter variant disrupts multisensory processing

Abstract

Altered sensory processing is observed in many children with autism spectrum disorder (ASD), with growing evidence that these impairments extend to the integration of information across the different senses (that is, multisensory function). The serotonin system has an important role in sensory development and function, and alterations of serotonergic signaling have been suggested to have a role in ASD. A gain-of-function coding variant in the serotonin transporter (SERT) associates with sensory aversion in humans, and when expressed in mice produces traits associated with ASD, including disruptions in social and communicative function and repetitive behaviors. The current study set out to test whether these mice also exhibit changes in multisensory function when compared with wild-type (WT) animals on the same genetic background. Mice were trained to respond to auditory and visual stimuli independently before being tested under visual, auditory and paired audiovisual (multisensory) conditions. WT mice exhibited significant gains in response accuracy under audiovisual conditions. In contrast, although the SERT mutant animals learned the auditory and visual tasks comparably to WT littermates, they failed to show behavioral gains under multisensory conditions. We believe these results provide the first behavioral evidence of multisensory deficits in a genetic mouse model related to ASD and implicate the serotonin system in multisensory processing and in the multisensory changes seen in ASD.

Figure 1

Behavioral task. (a) An outlined progression of the behavioral paradigm. (b) Above: a diagram of the operant chamber during the presentation of a congruent audiovisual stimulus (represented by the yellow color within the nose poke hole, where the LED was positioned) and by the active speaker. (b) Below: a schematic representation of the trial sequence and timing. LED, light-emitting diode.

Figure 2

Evaluating behavioral performance for wild-type and SERT Ala56 mice under unisensory training conditions. Unpaired t-tests demonstrated no significant differences between genotypes for either (a) accuracies (P=0.90) or (b) days to acquisition (P=0.66) under visual training conditions. Wild-type mice completed the visual task after 20.6±4.4 days with a final accuracy of 82.2±2.1%, whereas SERT Ala56 mice completed the visual training in 17.8±4.7 days with a final accuracy of 82.6±2.5%. Unpaired t-tests demonstrated no significant differences between wild-type and SERT animals in (c) accuracies (P=0.21) or (d) days to acquisition (P=0.52) under auditory training conditions. Wild-type animals completed the auditory training in 58.0±11.1 days and with a final accuracy of 70.8±1.4% and SERT Ala56 mice finished this task after 49.0±7.5 days with a final accuracy of 73.2±1.2%. SERT, serotonin transporter; WT, wild-type.

Figure 3

Behavioral accuracies for multisensory, visual and auditory conditions collapsed across stimulus durations. Overall accuracies for these collapsed conditions for wild-type animals were as follows: multisensory—76.4±1.71%, visual—67.3±1.98% and auditory 69.8±1.45%. Accuracies for SERT Ala56 animals were as follows: multisensory—68.9±1.99%, visual—63.3±1.68% and auditory 64.5±1.72%. Significant main effects of genotype (P=0.0013; F(1, 39=11.99)) and sensory modality (P<0.0001; F(2, 78=51.12)) were observed. Also, significant differences between wild-type and SERT Ala56 animals under multisensory (P<0.0001), visual (P=0.0215) and auditory conditions (P=0.0014) were observed. Behavioral performance was then evaluated within each genotype. For wild-type animals, significant differences between multisensory and visual conditions (P<0.0001), multisensory and auditory conditions (P<0.0001) and no significant differences between visual and auditory conditions (P=0.2000) were found. Similarly for SERT Ala56 mice, significant differences between the multisensory and visual conditions (P=0.0007), multisensory and auditory conditions (P=0.0093) and no significant differences between visual and auditory conditions (P=0.6816) were observed. The significant levels are as follows: (*P<0.05, **P<0.01, ****P<0.0001). SERT, serotonin transporter; WT, wild-type.

Figure 4

Evaluating multisensory gain across stimulus durations at both the group and individual performance levels. Wild-type animals demonstrated greater multisensory gain than SERT Ala56 animals at the group level at all stimulus durations (a). The values for multisensory gain for wild-type mice were as follows: 1 s—9.30%, 500 ms—9.74%, 300 ms—12.70%, 100 ms—6.90% and 50 ms—7.40%. Multisensory gain values for SERT Ala56 mice were as follows: 1 s—6.30%, 500 ms—6.20%, 300 ms—7.20%, 100 ms—3.14% and 50 ms—1.50%. Significant differences in accuracies under multisensory and the best unisensory conditions were observed at both the 500 ms (b) and 300 ms (c) stimulus durations for wild-type animals. At the 300 ms duration, a repeated measures two-way ANOVA demonstrated a significant main effect of sensory modality (P=0.0334; F(1, 7)=6.969) and a significant main effect of genotype (P=0.0421; F(1, 7)=6.159; c). Significant differences between multisensory and the best unisensory conditions were observed for wild-type mice (P=0.02) but not SERT Ala56 mice (P=0.36). No significant differences in behavioral accuracies were observed for SERT Ala56 mice for either the 500 ms (b) or 300 ms (c) stimulus duration. Black lines represent the group average performance under multisensory and the best unisensory conditions. Note the descending slope of these lines, which is apparent for wild-type animals at the 500 and 300 ms durations and is not observed for SERT Ala56 mice. The significant level is: (*P<0.05). ANOVA, analysis of variance; SERT, serotonin transporter; WT, wild-type.