Exploring a genetic intersection of autism and homeostatic synaptic plasticity

It is well established that homeostatic signaling systems interface with the mechanisms of developmental and learning-related plasticity to achieve stable yet flexible neural function and animal behavior. Experimental evidence from organisms as diverse as Drosophila, mice and humans demonstrates that homeostatic signaling systems stabilize neural function through the modulation of synaptic transmission, ion channel abundance and neurotransmitter receptor trafficking¹, ², ³, ⁴. At a fundamental level, if homeostatic plasticity is compromised, the nervous system is likely to be more sensitive to perturbations. Graeme Davis and his colleagues speculate that impaired homeostatic plasticity could contribute to autism by making the developing nervous system vulnerable to perturbations of any origin, including genetic, environmental or immunological stresses.

One possibility is that autism-linked genes are also essential for homeostatic plasticity. A second possibility is that mutations in genes associated with homeostatic plasticity may contribute to the phenotypic severity of autism-linked gene mutations. Davis and his colleagues plan to investigate this hypothesis by testing for genetic interaction between autism-linked gene mutations and homeostatic plasticity gene mutations in Drosophila.

Finally, Drosophila offers an opportunity to identify genetic loci that contribute to the phenotypic severity of an autism-linked gene mutation. Identifying such loci may reveal insights into how heterozygous, loss-of-function mutations cause severe phenotypic consequences in autism spectrum disorder. Together, these genetic screens may open the door to fundamentally new ideas regarding the progression and severity of autism, and to new potential avenues for therapeutic intervention.