What We Have Learned about Autism Spectrum Disorder from Valproic Acid

Figure 1

A schematic of some key molecular and cellular changes associated with VPA related to ASD neuropathology. Common clinicopathology associated with ASD is accelerated or early brain overgrowth and increased network excitability. Early or accelerated overgrowth may result from more synapses, increased denritic growth, and/or increased number of cells, while increased network excitability may result from hyperconnectivity and/or hyperplasticity of microcircuits, presumably driven by synaptic mechanisms (i.e., enhanced paired-pulse facilitation and long-term potentiation) that have been shown in rat brain both in vitro and in vivo following prenatal VPA exposure [56, 57]. All of these aspects are also likely regulated by histone acetylation (orange circles “Ac”) and/or histone methylation (green circles “Me”) and possibly DNA methylation (DNA methylation not shown). VPA has been shown to increase histone acetylation and histone methylation that can promote gene activation (symbolized by blue circle “Pol”; RNA polymerase). While VPA may disrupt the balance between excitatory and inhibitory neuronal activities through histone acetylation modulation [58], the role of histone methylation on VPA-related ASD neuropathology is much less clear. Increased connectivity and network excitability may further influence this process by activating metabotropic, ionotropic, and voltage-gated ion channels and subsequent intracellular signaling cascades.