Abstract
Sensory processing dysfunction (SPD) is present in most patients with intellectual disability (ID) and autism spectrum disorder (ASD). Silencing expression of the Fragile X mental retardation 1 (FMR1) gene leads to Fragile X syndrome (FXS), the most common single gene cause of ID and ASD. Drosophila have a highly conserved FMR1 ortholog, dfmr1. dfmr1 mutants display cognitive and social defects reminiscent of symptoms seen in individuals with FXS. We utilized a robust behavioral assay for sensory processing of the Drosophila stress odorant (dSO) to gain a better understanding of the molecular basis of SPD in FXS. Here, we show that dfmr1 mutant flies present significant defects in dSO response. We found that dfmr1 expression in mushroom bodies is required for dSO processing. We also show that cyclic adenosine monophosphate (cAMP) signaling via PKA is activated after exposure to dSO and that several drugs regulating both cAMP and cyclic guanosine monophosphate (cGMP) levels significantly improved defects in dSO processing in dfmr1 mutant flies.
Highlights
Sensory processing dysfunction (SPD) is a key symptom seen in 90% of individuals with intellectual disability (ID) and autism spectrum disorder (ASD) (Marco et al, 2011; Chang et al, 2014) where the response to a given stimulus is different from the typically developing population
In silico pathway analyses were performed with Ingenuity Pathway Analysis (IPA, Qiagen) to identify interactions with cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by genes associated with ASD from the SFARI Gene database and genes implicated in ID from published literature (Gilissen et al, 2014)
As cAMP signaling is required for CO2 sensing (Klengel et al, 2005) and cAMP signaling dysregulation is linked to Fragile X syndrome (FXS) early on in human (Berry-Kravis et al, 1984) and in Drosophila (Kanellopoulos et al, 2012), we investigated if cAMP regulation could be involved in the defective Drosophila stress odorant (dSO) response in dfmr1 mutants
Summary
Sensory processing dysfunction (SPD) is a key symptom seen in 90% of individuals with intellectual disability (ID) and autism spectrum disorder (ASD) (Marco et al, 2011; Chang et al, 2014) where the response to a given stimulus is different from the typically developing population. The most common clinical features of SPD are under-responsiveness, sensory seeking, auditory filtering, and tactile sensitivity (Tomchek and Dunn, 2007). This reflects that multiple senses are affected, including audition, touch, vision, and oral sensation (Kern et al, 2006). Some individuals with ASD will perceive sound much louder than typically developing individuals and this will affect their behavior. They will either block their ears or become increasingly anxious. We show that Drosophila dfmr mutant flies present significant defect in responding to dSO
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