OXYTOCIN NEURONAL DEVELOPMENT AND SOCIAL BEHAVIOR IN ZEBRAFISH: EFFECTS OF EARLY VALPROIC ACID EXPOSURE

Autism Spectrum Disorders (ASDs) are characterized by difficulties with social communication and repetitive behaviors, and, unfortunately, there is no effective treatment. Maternal use of the antiepileptic drug valproate during pregnancy is one of several established environmental risk factors for ASD. Zebrafish is a valuable vertebrate model for studying social brain development and for pharmacological screening. The neuropeptide oxytocin regulates social interactions in zebrafish as in many species. This study aims to describe oxytocin neuron development in zebrafish, and whether early valproate exposure alters oxytocin neuron number as well as social interactions later in life. Oxytocin neurons were investigated using an oxt:EGFP line. Brains were collected weekly from fish aged 2 dpf to juvenile age, and at adulthood, fixed, cryoprotected, and cleared with the CUBIC-L/R protocol. A subset of embryos was exposed to valproate (12.5 or 25 µM) at 10 hours post-fertilization for 48 hours and compared to non-exposed controls. Cleared brains were imaged by light-sheet fluorescence microscopy, and 3D datasets were processed and oxytocin neurons were quantified using Arivis Vision4D. Oxytocin neurons were first detected at 26 hpf and increased progressively across development and reached adult levels at approximately eight weeks of age. Interestingly, embryonal valproate exposure decreased the number of oxytocin neurons and modified social interactions at four weeks-of-age. In conclusion, the development of oxytocin neurons and sociability are hampered by the autism risk factor valproate in zebrafish, which provide exciting opportunities for in vivo-screening for drugs rescuing neuronal and behavioral aberrations of relevance for ASD.