Autism and other neurodevelopmental dissorders

    Autism is a devastating neurodevelopmental disease.  In the Giraldez Lab we have began investigating the genes linked to Autism with the goal of identifying the molecular, cellular and electrophysiological defects caused by these mutations in zebrafish embryos. While the analysis of Autism and other neurodevelopmental human syndroms might sound far fetched, there are tremendous advantages of using a vertebrate model system with rapid development and complex behavioral phenotypes, whose behaviour can be monitored in large numbers. More importantly we have adapted behavioural profiling with chemical screening to characterize the phenotypes of mutants and identify pharmacological compounds that might suppress the behavioural phenotypes and inform us of the pathways affected in these mutants with the ultimate goal of identifying supressor drugs for this syndrome.

miRNA ~30%

Y          >60%

   Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. Hoffman EJ, Turner KJ, Fernandez JM, Cifuentes D, Ghosh M, Ijaz S, Jain RA, Kubo F, Bill BR, Baier H, Granato M, Barresi MJ, Wilson SW, Rihel J, State MW, Giraldez AJ‡. Neuron. 2016 Feb 17;89(4):725-33.

        In a recent study (Hoffman et al., Neuron 2016) we have investigated the function of Cntnap2, a gene linked to Autism.  Using high-throughput behavioral profiling we identified nighttime hyperactivity in cntnap2 mutants, while pharmacological and neurodevelopmental assays reveal dysregulation of GABAergic and glutamatergic systems. Combining behavioral profiling with a pharmacological screening identified estrogenic compounds as phenotypic suppressors, suggesting that these compounds serve as modifiers of neural circuits disrupted in mutants. This study provides an entry point to characterize additional mutations associated with autism and define common suppressors as potential therapeutic agents for further investigation. Postdoctoral Position to Study Autism

Biran J & Levkowitz 2016