High-throughput screening for small psycho-active molecules in zebrafish embryos

Here, we describe a simple, behaviour-based approach to identify in vivo novel psycho-active molecules in zebrafish embryos. Using an automated behaviour recording system, we have developed a protocol that makes it possible to distil drug-induced behaviour changes into a series of quantifiable parameters, which allow inferring the psycho-activity of tested molecules.

Interest / Relevance: Small psychoactive molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, very few novel psycho-active drugs only have been discovered in last decades and most of them were discovered serendipitously. Given the unmet need for new psycho-active molecules, we have developed a simple approach that combined an automated motility recording system with the biological complexity of living animals.
Keywords: Zebrafish , Small molecules , Psycho-active molecule , High-throughput in vivo screening , Vertebrate model
Scientist's name: Nadia SOUSSI-YANICOSTAS
1. G houmid D revillon S M Alavi-Naini Bondurand M Rio A Briand-Suleau M Nasser L Goodwin P Raymond C Yanicostas M Goossens S Lyonnet D Mowat J Amiel N Soussi-Yanicostas I Giurgea. rnZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. rnHum Mol Genet. 2013 rnrn2. Yanicostas C Barbieri E Hibi M Brice A Stevanin G Soussi-Yanicostas N.rnRequirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.rnPLoS One. 2012;7(11).rnrn3. Martin E Yanicostas C Rastetter A Alavi Naini SM Maouedj A Kabashi E Rivaud-Péchoux S Brice A Stevanin G Soussi-Yanicostas N.rnSpatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish.rnNeurobiol Dis. 2012 Dec;48(3):299-308
Detailed technology overview: We have established a simple, behaviour-based approach to identify in vivo novel psychoactive molecules using zebrafish embryos. Indeed, high-intensity light stimulus elicits a stereotypic series of motor behaviours in zebrafish embryos, the photomotor response (PMR), which can be divided in four phases: a pre-stimulus phase, a latency phase, an excitation phase and a refractory phase. Interestingly, diverse classes of psychoactive molecules induce distinct, quantifiable and highly reproducible modifications of the PMR. In turn, these modifications make it possible to classify psychoactive drugs and to infer their activity. We have established a screening procedure using the PMR and an automated behaviour recording platform that allows to record the motility of hundreds embryos simultaneously in 96-well plates. This protocol allows to rapidly identify new psychotropic molecules and to predict their molecular targets, toxicity and psycho-activity.

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