Valproic Acid Affects Neuronal Specification and Differentiation During Early Optic Tectum Development of 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, while proliferation of the OT neuroepithelium continued, neuronal specification stalled. This was followed by impairment of neurite extension and complexity, suggesting that in addition to neurogenesis, VPA treatment affects axonogenesis and dendritogenesis. 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.

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

“…This coincides with the period of VPA exposure in this study, suggesting that the drug has significant effects on cellular organization during cerebellar histogenesis. The observed behavioral and morphological phenotypes align with characteristics associated with ASD, such as reduced brain size and dysregulation of neuronal proliferation and migration [51][52][53][54][55]. Previous studies delving into the deregulation of neuronal proliferation due to VPA exposure in embryo zebrafish demonstrated the impact on the upregulation of the Notch pathway, which is also involved in cerebellar histogenesis [12].…”

“…This could be attributed to changes in genes like Shank3, known for its involvement in synapse formation and frequently altered in individuals with ASD and in response to VPA exposure [58][59][60]. Regarding this, Shank3 is a protein that plays a major role in the formation and maintenance of synapses, especially in the cerebellum, and is often found to be altered in individuals with ASD and in the VPA zebrafish model [39,[49][50][51][52][53][54][55][56][57][58][59][60]. Consequently, it has been proposed as one of the genetic alterations of significant importance in ASD [25].…”

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

“…This coincides with the period of VPA exposure in this study, suggesting that the drug has significant effects on cellular organization during cerebellar histogenesis. The observed behavioral and morphological phenotypes align with characteristics associated with ASD, such as reduced brain size and dysregulation of neuronal proliferation and migration [62][63][64][65][66].…”

“…This could be attributed to changes in genes like Shank3, known for its involvement in synapse formation and frequently altered in individuals with ASD and in response to VPA exposure [62,69,70]. Regarding this, Shank3 is a protein that plays a major role in the formation and maintenance of synapses, especially in the cerebellum, and is often found to be altered in individuals with ASD and in VPA zebrafish model [66,69,70]. Consequently, it has been proposed as one of the genetic alterations of significant importance in ASD [25].…”