Loss of NF1 in Drosophila larvae causes tactile hypersensitivity and impaired synaptic transmission at the neuromuscular junction.
Alex DysonMegan RyanShruti GargD Gareth EvansRichard A BainesPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2022)
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition in which the mechanisms underlying its core symptomatology are largely unknown. Studying animal models of monogenic syndromes associated with ASD, such as neurofibromatosis type 1 (NF1), can offer insights into its aetiology. Here, we show that loss of function of the Drosophila NF1 ortholog results in tactile hypersensitivity following brief mechanical stimulation in the larva (mixed sexes), paralleling the sensory abnormalities observed in individuals with ASD. Mutant larvae also exhibit synaptic transmission deficits at the glutamatergic neuromuscular junction (NMJ), with increased spontaneous but reduced evoked release. While the latter is homeostatically compensated for by a postsynaptic increase in input resistance, the former is consistent with neuronal hyperexcitability. Indeed, diminished expression of NF1 specifically within central cholinergic neurons induces both excessive neuronal firing and tactile hypersensitivity, suggesting the two may be linked. Furthermore, both impaired synaptic transmission and behavioural deficits are fully rescued via knockdown of Ras proteins. These findings validate NF1 -/- Drosophila as a tractable model of ASD with the potential to elucidate important pathophysiological mechanisms. Significance statement: Autism spectrum disorder (ASD) affects 1-2% of the overall population and can considerably impact an individual's quality of life. However, there are currently no treatments available for its core symptoms, largely due to a poor understanding of the underlying mechanisms involved. Examining how loss of function of the ASD-associated NF1 gene affects behaviour and physiology in Drosophila may shed light on this. In this study, we identify a novel, ASD-relevant behavioural phenotype in NF1 -/- larvae, namely an enhanced response to mechanical stimulation, which is associated with Ras-dependent synaptic transmission deficits indicative of neuronal hyperexcitability. Such insights support the use of Drosophila NF1 models in ASD research, and may provide outputs for genetic or pharmacological screens in future studies.
Keyphrases
- autism spectrum disorder
- signaling pathway
- lps induced
- attention deficit hyperactivity disorder
- intellectual disability
- pi k akt
- nuclear factor
- oxidative stress
- inflammatory response
- traumatic brain injury
- genome wide
- cell proliferation
- spinal cord
- toll like receptor
- aedes aegypti
- drug induced
- spinal cord injury
- physical activity
- brain injury
- working memory
- prefrontal cortex
- gene expression
- depressive symptoms
- high throughput
- single cell
- weight loss
- drosophila melanogaster
- sleep quality