Loss of NF1 in Drosophila Larvae Causes Tactile Hypersensitivity and Impaired Synaptic Transmission at the Neuromuscular Junction

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 etiology. 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 behavioral deficits are fully rescued via knock-down of Ras proteins. These findings validate NF1-/- Drosophila as a tractable model of ASD with the potential to elucidate important pathophysiological mechanisms.

Automated summary

This study investigates the relationship between neurofibromatosis type 1 (NF1) and autism spectrum disorder (ASD) using a Drosophila model. It shows that loss of function of the NF1 gene in flies leads to tactile hypersensitivity and synaptic transmission deficits, resembling sensory abnormalities seen in individuals with ASD. The study suggests that NF1 deficiency may cause neuronal hyperexcitability and that decreased NF1 expression results in excessive neuronal firing and tactile hypersensitivity, potentially linking these two aspects. Knock-down of Ras proteins rescues both synaptic transmission deficits and behavioral deficits.