Autism spectrum disorder (ASD) arises from diverse genetic and environmental risk factors. Drosophila melanogaster provides a powerful and under-utilized system to dissect the molecular pathways that underlie the phenotypes associated with these gene and environment products. Here, we explore mitochondrial and synaptic dynamics in a gene-environment model of ASD. Our genetic arm employs a human neuroligin 1 (NGLN1) H795Y variant associated with ASD, while our environmental arm involves developmental exposure to valproic acid (VPA), a mitochondrial stressor and prenatal risk factor of ASD. To examine convergence, NGLN1 variant flies were also raised in VPA. ASD phenotypes were captured through a validated behavioral assay called the social space assay. Synaptic functional plasticity was quantified at the larval neuromuscular junction (NMJ) by measuring miniature excitatory junction potentials (mEJPs), and structural plasticity was visualized by confocal imaging of ghost boutons. Mitochondrial involvement was further examined with fluorescent reporters of membrane potential and the antioxidant n-acetylcysteine. Preliminary results showed both sex and dose-dependent changes in social spacing in VPA-exposed flies, as well as sex-dependent effects in NLGN1 mutant flies. Within conditions, alterations in mitochondrial membrane potential and mEJP frequency were also observed. Together, these approaches allow us to dissect how mitochondrial dysfunction and synaptic adhesion perturbations interact to shape neural circuit output and behavior, providing new insight into metabolic contributions to neurodevelopmental disorders.
Silva et al. (Sun,) studied this question.