Abstract
Background: Valproic acid (VPA) is an anti-convulsant drug used to treat seizures and a variety of neural pathologies. Studies have shown that VPA exposure in rodent embryos leads to behavioral characteristics similar to those in humans with autism spectrum disorder (ASD). Utilizing this rodent model of ASD, research has led to a recognized mechanism of action of VPA involving brain overgrowth and hyperconnectivity, likely caused by epigenetic alteration of gene expression through inhibition of histone deacetylases.Objective: To gain further insight concerning this mechanism we modeled the development of neural connectivity at the cellular level.Method: We cultured dorsal root ganglia (DRGs) taken from eight-day old chick embryos in a range of VPA concentrations and investigated aspects of neuronal structure and behavior. DRGs were cultured 48 hours, fixed, and immunostained to reveal the locations of neural networks with synaptic vesicles.Results: We found a concentration-dependant relationship with a significant increase in neurite length in VPA concentrations of 1 and 2 mM, and the effect was still present though weaker at 4 and 6 mM. Trichostatin A (TSA), another histone deacetylase inhibitor, caused similar responses. To further characterize the effects, we carried out time-lapse imaging of growth cones of extending neurites. We found that VPA increased the area changing activity of growth cones, augmenting their exploratory capabilities, along with significantly enhancing overall advancement, thus increasing the ability to extend and form synapses. The average total of stained synaptic areas surrounding each cultured DRG was significantly increased in 6 mM VPA, but not significantly at the lower concentrations compared to controls.Conclusion: Our results show that VPA, at 1 mM and higher concentrations increases growth cone activity, and increases the number of neurites and their extension, a neurotrophic effect. It also increases synaptogenesis at 6 mM, supporting the theory of developmental neuronal overgrowth.
Highlights
The symptoms of autism spectrum disorder (ASD) can be observed following exposure to the anti-seizure drug Valproic acid (VPA)
We found that VPA concentration affected the neurite number formed per dorsal root ganglia (DRG) and neurite length maximally at 2.0 mM, and that higher concentration had lesser effect, suggesting an upper limit to the response
We have presented evidence that VPA stimulates the formation of more neurites with greater length, and has a maximum effect at 2 mM
Summary
The symptoms of autism spectrum disorder (ASD) can be observed following exposure to the anti-seizure drug VPA. According to data from the United States Center for Disease Control and Prevention [2] the incidence rate was one in 150 births in 2002, one in 68 births in 2010, and had climbed to one in 59 by 2014 Within this data, the CDCP reported that ASD is about four times more common among boys than among girls [2]. Studies have shown that VPA exposure in rodent embryos leads to behavioral characteristics similar to those in humans with autism spectrum disorder (ASD). Utilizing this rodent model of ASD, research has led to a recognized mechanism of action of VPA involving brain overgrowth and hyperconnectivity, likely caused by epigenetic alteration of gene expression through inhibition of histone deacetylases. It increases synaptogenesis at 6 mM, supporting the theory of developmental neuronal overgrowth
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