Abstract
Maternal exposure to the valproate short-chain fatty acid (SCFA) during pregnancy is known to possibly induce autism spectrum disorders (ASDs) in the offspring. By contrast, case studies have evidenced positive outcomes of this anticonvulsant drug in children with severe autism. Interestingly, the same paradoxical pattern applies to the IL-17a inflammatory cytokine involved in the immune system regulation. Such joint apparent contradictions can be overcome by pointing out that, among their respective signaling pathways, valproate and IL-17a share an enhancement of the “type A monoamine oxidase” (MAOA) enzyme carried by the X chromosome. In the Guided Propagation (GP) model of autism, such enzymatic rise triggers a prenatal epigenetic downregulation, which, without possible X-inactivation, and when coinciding with genetic expression variants of other brain enzymes, results in the delayed onset of autistic symptoms. The underlying imbalance of synaptic monoamines, serotonin in the first place, would reflect a mismatch between the environment to which the brain metabolism was prepared during gestation and the postnatal actual surroundings. Following a prenatal exposure to molecules that significantly elicit the MAOA gene expression, a daily treatment with the same metabolic impact would tend to recreate the fetal environment and contribute to rebalance monoamines, thus allowing proper neural circuits to gradually develop, provided behavioral re-education. Given the multifaceted other players than MAOA that are involved in the regulation of serotonin levels, potential compensatory effects are surveyed, which may underlie the autism heterogeneity. This explanatory framework opens up prospects regarding autism prevention and treatment, strikingly in line with current advances along the gut microbiome–brain axis.
Highlights
Living organisms do not passively undergo inputs from their biological environment
The Guided Propagation (GP) theory puts forward a 5-HT ‘‘noise’’ that improperly remains into the synaptic cleft during sleep whatever the baseline level of 5-HT at the beginning of every sleep cycle, relatively irrespective of the online regulation exerted by the players introduced above
Possible enzymatic disruptions during gestation are substantiated by the finding of chemical factors that overexpress the monoamine oxidase (MAOA) enzyme and strikingly entail similar paradoxical effects
Summary
Living organisms do not passively undergo inputs from their biological environment. Whether air particle, radiation, food, or drug, any ambient stimulus generates different net effects depending on both its strength and context of intrusion into the human body. In case of epigenetic masking (i.e., X-inactivation in women) or genetic variant (low/medium COMT), the MAOA downregulation is silently transferred to the offspring where it may occur in a different genetic context leading to overt autism (case 2 above) According to this possible etiology of ASD (Figure 3), only the erasure of specific epigenetic traits supporting the MAOA downregulation could permanently reverse the brain enzymatic imbalance at issue. Besides a common lowered diversity of the autistic children microbiome, a trend seems to emerge from existing data, reminiscent of the alternative ASD inducer/remedy represented here by cytokines and SCFAs. In absence of medical intervention involving antibiotics, the microbiota would develop along the inflammatory arm and its associated digestive troubles: any shift towards a gut pro-inflammatory state can in turn trigger the activation of neuro-inflammatory responses in the brain (Golubeva et al, 2017), with potential improvement of ASD. Together with the immune system, the microbiome may require follow-up when planning pregnancy, as part of a strategy aimed at limiting autism development (Paysour et al, 2019)
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