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  • Here we propose a hypothesis that explains


    Here, we propose a hypothesis that explains how a mild MIR can contribute to azidothymidine overgrowth by enhancing neural stem and progenitor cell proliferation through the dysregulation of cellular redox signaling. This hypothesis is based on evidence that reactive oxygen species (ROS) at nontoxic levels can increase stem cell self-renewal and neurogenesis through the reversible inactivation of PTEN protein and subsequent enhancement of PI3K pathway activation (Le Belle et al., 2011). The MIR stimulates the generation of ROS through the actions of various cytokines and activation of the NADPH oxidase (NOX) enzyme, which enhances signal transduction for many growth and trophic factors that are important for normal brain development (Beloosesky et al., 2012; Clement et al., 2010; Chen et al., 2011). We hypothesize that the MIR activates NOX, which in turn elevates cellular ROS levels and leads to increased stem and progenitor proliferation during early brain development, resulting in macrocephaly and autism. This pathological process would be expected to be enhanced by interaction with certain genetic susceptibilities, such as heterozygous PTEN mutations.
    Discussion The fact that mild brain overgrowth is the most common endophenotype in ASD suggests that the mechanism underlying this pervasive accelerated growth could result from the convergence of different genetic susceptibilities in combination with environmental stimulation onto common pathways. It is our theory that a large subset of individuals with autism and mild brain overgrowth has the final common pathway of enhanced ROS-signaling with resultant PI3K/AKT pathway stimulation, even though different genetic mutations and immune-activating environmental factors may contribute to this activation. The types of genetic mutations that could impact the cellular redox balance in response to MIR include alterations in antioxidant genes, immune-response genes, and ROS-generating genes (e.g., NADPH oxidase), or in genes encoding proteins that can be inactivated and regulated by ROS, such as PTEN. Many of these mutations have already been identified in ASD populations (Luo et al., 2012; Klein et al., 2013; Rose et al., 2012; Voineagu et al., 2011). Clearly, not every maternal immune-activating event during early pregnancy results in the development of autism, raising the question as to what influences the deleterious fetal response to MIR in those infants who do develop autism. In our MIR model, we found that not all pups in a litter experienced brain overgrowth and this was not related to gender, consistent with what others have found regarding autoimmune-related brain overgrowth in both children (Nordahl et al., 2013) and primates (Bauman et al., 2013). Furthermore, although we found that rescue of MIR-induced brain overgrowth and pathway activation was possible with prenatal NOX inhibition, it also had the negative effect of causing brain undergrowth in some pups. Thus, there is a heterogeneous response to an altered redox balance during brain development among offspring, suggesting that the effects of this dysregulation may depend on underlying individual susceptibilities. Here, we examined a specific genetic susceptibility, PTEN. Mutations in PTEN affect only 1 in 242,063 individuals in the general population, but are found in approximately 4% of ASD individuals (Hobert et al., 2013; Varga et al., 2009). As a proof of principle, we have shown that PTEN heterozygosity interacts with MIR to produce even greater brain overgrowth than can be induced in WT mice. This is in agreement with previous evidence that heterozygous PTEN deletion interacts with ROS stimulation by enhancing stem cell proliferation even more than can be achieved in WT cells (Le Belle et al., 2011). Similarly, TSC haploinsufficiency has been shown to interact with MIR to cause autism-related behaviors in pups (Ehninger et al., 2012). Although our MIR model most closely replicates key phenotypes associated with autism, there is a considerable overlap of some genetic and environmental risk factors, brain pathology, and behavioral abnormalities with other neurodevelopmental disorders, such as schizophrenia (Fatemi et al., 2002). Consequently, MIR-mediated brain overgrowth and the underlying cellular and signaling mechanisms that we have identified could represent a final common pathway for the abnormal phenotypes shared by several neuropsychiatric disorders.