Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in humans characterized by complex behavioral deficits, including intellectual disability, impaired social interactions, and hyperactivity. ASD exhibits a strong genetic component with underlying multigene interactions. Candidate gene studies have shown that the neurobeachin (NBEA) gene is disrupted in human patients with idiopathic autism (Castermans et al., 2003). The NBEA gene spans the common fragile site FRA 13A and encodes a signal scaffold protein (Savelyeva et al., 2006). In mice, NBEA has been shown to be involved in the trafficking and function of a specific subset of synaptic vesicles. (Medrihan et al., 2009; Savelyeva et al., 2006). Rugose (rg) is the Drosophila homolog of the mammalian and human NBEA. Our previous genetic and molecular analyses have shown that rg encodes an A kinase anchor protein (DAKAP 550), which interacts with components of the epidermal growth factor receptor or EGFR and Notch-mediated signaling pathways, facilitating cross talk between these and other pathways (Shamloula et al., 2002). We now present functional data from studies on the larval neuromuscular junction that reveal abnormal synaptic architecture and physiology. In addition, adult rg loss-of-function mutants exhibit defective social interactions, impaired habituation, aberrant locomotion, and hyperactivity. These results demonstrate that Drosophila NBEA (rg) mutants exhibit phenotypic characteristics reminiscent of human ASD and thus could serve as a genetic model for studying ASDs.

Keywords:

• Autism spectrum disorder
• Drosophila
• neurobeachin
• neuromuscular junction
• rugose
• synaptic development

Acknowledgements

We thank Dr. Wes Gruber (Columbia University) for the generous use of his larval tracking equipment. We are grateful to Dr. Sally Hoskins (CCNY) for comments and suggestions on the manuscript. Research presented here was supported by grants from the NIH (T.V and C.-F. W). A.W. was supported by NIH-RISE and LSAMP grants at the City College. A.F.S. was supported by PSC-CUNY Awards, jointly funded by the Professional Staff Congress, and the City University of New York and by internal funding from Western University, Ontario, Canada. R.W.F. was supported by a scholarship from the Alliance/Merck Ciencia Hispanic Scholars Program for STEM College students. The work at City College was supported by NIH-RCMI grant # 8G12MD007603–29.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.