Dissecting the Genetics of Autism Spectrum Disorders: A Drosophila Perspective

Abstract

Autism Spectrum Disorder (ASD) is a complex group of multi-factorial developmental disorders that leads to communication and behavioral defects. Genetic alterations have been identified in around 20% of ASD patients and the use of genetic models, such as Drosophila melanogaster, has been of paramount importance in deciphering the significance of these alterations. In fact, many of the ASD associated genes, such as FMR1, Neurexin, Neuroligins and SHANK encode for proteins that have conserved functions in neurons and during synapse development, both in humans and in the fruit fly. Drosophila is a prominent model in neuroscience due to the conserved genetic networks that control neurodevelopmental processes and to the ease of manipulating its genetics. In the present review we will describe recent advances in the field of ASD with a particular focus on the characterization of genes where the use of Drosophila has been fundamental to better understand their function.

Keywords: Drosophila; FMR1; autism (ASD); dopamine; mGlu receptor 5; neurexin; neuroligins; shank.

FIGURE 1

A schematic view of a glutamatergic synapse, showing the proteins analyzed in this review and implicated in Autism Spectrum Disorder (ASD). Neurexin and neuroligin are located in pre- and post-synaptic sites where they interact with multiple partners for mediating synapse development and maturation. Neuroligins binds to PSD-95, which interacts indirectly with Shank by intracellular complexes containing also Guanylate-kinase-associated protein (GKAP). dNlg1 and 3 act mostly in pre-synaptic terminals while dNlg2 functions is both pre- and post-synaptic ends. Other proteins involved in the synaptic establishment are FMRP RNA-binding and Thickveins (Tkv), that are expressed in both synaptic sites, mGlutR5 and Wishful thinking (Wit) that are found specifically on the post-synaptic membrane. Glass Bottom Boat (Gbb) is the ligand of both Tkv and Wit, homologous to vertebrate bone morphogenic protein (BMP).

FIGURE 2

A diagram showing the flow-through to study the molecular mechanisms of ADS using Drosophila. From the initial identification of human genes associated to ADS, to the characterization of their functions using GOF and LOF experiments, applying the milieu of genetic tools available (see Table 1). Using transgenic animals, functional and behavioral studies are used to provide the translational benefits necessary to identify or clarify the function of the gene in humans. Moreover, the fruit fly can be easily adapted to perform reverse genetics or chemical screens to identify novel genes or therapeutic drugs in ADSs.