22263
Abnormal Contrast Responses in a Fruit-Fly Model of Autism
Sensory abnormalities, such as hypersensitivity to bright lights and loud sounds, are a common symptom in human autism spectrum conditions (ASC). Here we investigate a potential biological and genetic underpinning of these effects using a fruit fly model of autism. Mutations in the sodium-hydrogen exchanger gene Nhe9 have been linked with ASC in humans (Morrow et al, 2008), and the fly homologue is the Nhe3 gene.
Objectives:
We investigated whether Nhe3 mutations affect visual responses in Drosophila.
Methods:
Two stocks of Drosophila were used: a mutant (KG) and a gene deficiency (DF). Matched eye-colour controls were used. SSVEP (Steady State Visual Evoked Potential) electroretinograms (Afsari et al, 2014) were recorded at 3 and 14 days old (i.e. juvenile and adult flies). The stimulus was a flickering blue LED, with 12Hz temporal frequency and 7 contrast levels (0-69%). The mean amplitudes for each contrast level for the target frequency (1F, primarily the photoreceptor response) and second harmonic (2F, primarily post-retinal neural responses) were calculated. We tested at least 12 flies of each genotype and age, and averaged amplitudes across all individuals.
Results:
All Nhe3 mutant genotypes differed substantially from wild type controls and heterozygotes (mutant-wild type crosses). The key finding is that young (3-day-old) KG homozygote flies show reduced response amplitudes at 1F and 2F (both 30% less than wild types). This was confirmed by testing the KG/DF cross: at 3 days these also had lower response amplitudes at both 1F and 2F. Older (14 days) KG and KG/DF flies had still had reduced 2F responses but their 1F responses were bigger than the controls. The 1F responses of 14-day-old flies were bigger than the 3-day-old flies.
Conclusions:
ERG response amplitudes differ between ASD model fruit flies and wild type controls at both 3 and 14 days of age. Fourteen-day-old mutants show increased sensitivity in photoreceptors as indicated by higher 1F amplitude but decreased response from more complex cells (lamina neurons) as evidenced by their lower 2F amplitudes. This suggests that the transfer from photoreceptors to neurons higher up in the visual stream is reduced. Our results demonstrate that the Nhe3 gene has a critical impact on multiple stages of the visual pathway, and may also mediate neuronal health and function more widely throughout the nervous system. In a companion study, we report analogous effects in EEG data from human adults with a clinical ASD diagnosis (compared with age-matched controls), and in the normal population as a function of autistic traits. The fly data therefore provide a possible genetic model for sensory abnormalities in human autism.