Autism sensory dysfunction in an evolutionarily conserved system

Abstract

There is increasing evidence for a strong genetic basis for autism, with many genetic models being developed in an attempt to replicate autistic symptoms in animals. However, current animal behaviour paradigms rarely match the social and cognitive behaviours exhibited by autistic individuals. Here, we instead assay another functional domain-sensory processing-known to be affected in autism to test a novel genetic autism model in Drosophila melanogaster. We show similar visual response alterations and a similar development trajectory in Nhe3 mutant flies (total n = 72) and in autistic human participants (total n = 154). We report a dissociation between first- and second-order electrophysiological visual responses to steady-state stimulation in adult mutant fruit flies that is strikingly similar to the response pattern in human adults with ASD as well as that of a large sample of neurotypical individuals with high numbers of autistic traits. We explain this as a genetically driven, selective signalling alteration in transient visual dynamics. In contrast to adults, autistic children show a decrease in the first-order response that is matched by the fruit fly model, suggesting that a compensatory change in processing occurs during development. Our results provide the first animal model of autism comprising a differential developmental phenotype in visual processing.

Keywords: Drosophila; animal model; autism; sensory processing; visual system.

Figure 1.

Human and Drosophila steady-state electrophysiology methods. (a) Left panel illustrates the experimental set-up for fruit fly electrophysiology (see Drosophila electroretinography for more details). Right panel shows the square wave stimulus trace flickering at 12 Hz (top), example electrophysiological responses over time (middle) and Fourier-transformed response amplitudes in the frequency domain (bottom). (b) Left panel illustrates the experimental set-up for adult participants, who were presented with a grid of sinusoidal gratings flickering at 7 Hz while ssVEPs were recorded with a 64-channel EEG cap (top). SSVEPs were measured from occipital electrode Oz (blue circle) where the highest first harmonic amplitude was centred (AQ adults, bottom left, ASD adults, bottom right). Right panel shows the stimulus trace (top), example responses in the time domain (middle) and in the frequency domain (bottom). (c) Shows equivalent experimental set-up, stimulus and response traces for the children's dataset. (Online version in colour.)

Figure 2.

Older ASD-mimic flies and autistic humans show reduced visual responses in the transient component. (a) Contrast response functions for adult Nhe3 mutant flies (Nhe3^KG08307 homozygotes, red squares and Nhe3^KG08307 /Df(2 L)BSC187, purple diamonds) were similar at the first harmonic (a one-way ANOVA showed no effect of group F_2,33 = 0.05, p = 0.95) but (b) responses were reduced for P/P (simple contrast, p = 0.025) and P/Df mutants compared to controls at the second harmonic (simple contrast p = 0.001; ANOVA group effect F_2,33 = 6.71, p < 0.01). (c) Ratios between frequencies $(1\mathrm{F}-2\mathrm{F}/1\mathrm{F}+2\mathrm{F})$ were significantly higher for P/P (p < 0.001) and for P/Df (p < 0.0001) than for the control genotype. First harmonic responses were also similar for the (d) high AQ and low AQ groups and (g) for autistic and neurotypical adults. However, second harmonic responses were reduced for both (e) adults with high AQ and (h) autistic adults compared to controls. (f,i) The ratio between harmonics was also higher in both experimental groups compared to controls (p = 0.005 and p = 0.04, respectively). Curved lines are hyperbolic function fits to the data. Frequency ratios are baselined in respect to the mean over groups of each comparison for display purposes. Error bars in all panels represent ± s.e.m.

Figure 3.

Young ASD-mimic flies and autistic children show reduced visual responses in the sustained component. (a) Young fruit flies showed reduced responses at the first harmonic (F_2,33 = 3.73, p = 0.035) with P/P and P/Df flies showing a significant difference from control flies (respectively, p = 0.016 and p = 0.040). (b) There was also a significant effect of genotype at the second harmonic (F_2,33 = 3.39, p = 0.046). P/Df flies showed a significant difference from control flies (p = 0.018), however, P/P showed a non-significant difference from controls (p = 0.064). (c) The flies had normal frequency ratios. (d) Autistic children also showed reduced first harmonic (t₂₈ = 2.065, p = 0.048) but (e) not second harmonic responses (t₂₈ = 1.26, p = 0.22) and (f) had frequency ratios similar to that of control children (t₂₈ = 1.21, p = 0.24). Curved lines are hyperbolic function fits to the data. Frequency ratios are baselined in respect to the mean over groups of each comparison for display purposes. Error bars in all panels represent ± s.e.m. (Online version in colour.)

Figure 4.

Positive relationship between the number of autistic traits and first/second harmonic ratio. Scatterplot showing a significant positive relationship between AQ scores and frequency ratios in the 100 neurotypical adult dataset indicating a gradual increase in response differences with the number of reported autistic traits. The black line indicates the regression line of best fit. Shaded grey areas show histograms of AQ scores and frequency ratios. Blue–red colour transition indicates number of AQ traits with participants split by median into low and high AQ groups as presented in figure 2. (Online version in colour.)