Loss of neurexin-1 in Drosophila melanogaster results in altered energy metabolism and increased seizure susceptibility.

Although autism is typically characterized by differences in language, social interaction and restrictive, repetitive behaviors, it is becoming more well known in the field that alterations in energy metabolism and mitochondrial function are comorbid disorders in autism. The synaptic cell adhesion molecule, neurexin-1 (NRXN1), has previously been implicated in autism, and here we show that in Drosophila melanogaster, the homologue of NRXN1, called Nrx-1, regulates energy metabolism and nutrient homeostasis. First, we show that Nrx-1-null flies exhibit decreased resistance to nutrient deprivation and heat stress compared to controls. Additionally, Nrx-1 mutants exhibit a significantly altered metabolic profile characterized by decreased lipid and carbohydrate stores. Nrx-1-null Drosophila also exhibit diminished levels of nicotinamide adenine dinucleotide (NAD+), an important coenzyme in major energy metabolism pathways. Moreover, loss of Nrx-1 resulted in striking abnormalities in mitochondrial morphology in the flight muscle of Nrx-1-null Drosophila and impaired flight ability in these flies. Further, following a mechanical shock Nrx-1-null flies exhibited seizure-like activity, a phenotype previously linked to defects in mitochondrial metabolism and a common symptom of patients with NRXN1 deletions. The current studies indicate a novel role for NRXN1 in the regulation of energy metabolism and uncover a clinically relevant seizure phenotype in Drosophila lacking Nrx-1.

Loss of Drosophila FMRP leads to alterations in energy metabolism and mitochondrial function.

Fragile X Syndrome (FXS), the most prevalent form of inherited intellectual disability and the foremost monogenetic cause of autism, is caused by loss of expression of the FMR1 gene . Here, we show that dfmr1 modulates the global metabolome in Drosophila. Despite our previous discovery of increased brain insulin signaling, our results indicate that dfmr1 mutants have reduced carbohydrate and lipid stores and are hypersensitive to starvation stress. The observed metabolic deficits cannot be explained by feeding behavior, as we report that dfmr1 mutants are hyperphagic. Rather, our data identify dfmr1 as a regulator of mitochondrial function. We demonstrate that under supersaturating conditions, dfmr1 mutant mitochondria have significantly increased maximum electron transport system (ETS) capacity. Moreover, electron micrographs of indirect flight muscle reveal striking morphological changes in the dfmr1 mutant mitochondria. Taken together, our results illustrate the importance of dfmr1 for proper maintenance of nutrient homeostasis and mitochondrial function.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.

Deciphering discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts.

Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. In addition to its canonical definition as a neurodevelopmental disease, recent findings in the clinic suggest that FXS is a systemic disorder that is characterized by a variety of heterogeneous phenotypes. Efforts to study FXS pathogenesis have been aided by the development and characterization of animal models of the disease. Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatially and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients.