Valproic acid affects neurogenesis during early optic tectum development in zebrafish

Abstract

The mammalian superior colliculus and its non-mammalian homolog, the optic tectum (OT), are midbrain structures that integrate multimodal sensory inputs and guide non-voluntary movements in response to prevalent stimuli. Recent studies have implicated this structure as a possible site affected in Autism Spectrum Disorder (ASD). Interestingly, fetal exposure to valproic acid (VPA) has also been associated with an increased risk of ASD in humans and animal models. Therefore, we took the approach of determining the effects of VPA treatment on zebrafish OT development as a first step in identifying the mechanisms that allow its formation. We describe the normal OT development during the first 5 days of development and show that in VPA treated embryos, neuronal specification and neuropil formation was delayed. VPA treatment was most detrimental during the first three days of development and did not appear to be linked to oxidative stress. In conclusion, our work provides a foundation for research into mechanisms driving OT development, as well as the relationship between the OT, VPA, and ASD.

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder

“…Prenatal exposure to VPA in cynomolgus monkey at gestational day 26, which is an equivalent period in murine models, found a decreased neurogenesis and fewer cells in the cerebellar external granular layer and layers II and IV of the prefrontal cortex (PFC) [ 185 ]. Zebrafish embryos exposed to VPA after eight hours post fertilization showed an increased proliferation rate [ 193 ] and reported on this model delayed neurogenesis NeuroD1 disruption on the optic tectum, a brain region with homology to the superior colliculus in humans [ 232 , 233 ]. In addition, studies in vitro have helped us understand VPA’s effects on neurogenesis and cell growth.…”

“…Axonal ectopic branches and excessive abnormal branching increased in a VPA concentration-dependent pattern during the gestational development of zebrafish [ 261 ]. In contrast, at higher doses, VPA induces delayed neuropil formation and axogenesis [ 232 ]. Interestingly, VPA induces abnormal differentiation of serotoninergic neurons by downregulating the proneural ascl1b gene, a mechanism mediated by HDAC1 inhibition [ 262 ].…”

Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism

“…Additionally, prenatal exposure to valproic acid, which, clinical evidence indicate, has a strong association with autism [ 71 , 72 ], enhanced untimely embryonic neurogenesis in mice, leading to a depletion of the neural precursors and resulting in decreased levels of adult hippocampal neurogenesis [ 73 ]. In zebrafish embryos, valproic acid adversely affected neurogenesis in the optic tectum [ 74 ], reduced midbrain size, and reduced the number of neuronal progenitors, along with perturbations in the secondary motor neuron neurite development [ 75 ]. Modeling the genetic as well as environmental aspects in zebrafish embryos can offer an ideal system for an in-depth investigation of the potential mechanisms of autism development, since manipulation of individual risk genes in these embryos may lead to the identification of phenotype-based mechanistic pathways.…”