PMC7686807_01
Puzzle of autism, according to the Guided Propagation (GP) model. Pieces containing a green label in italics represent hypotheses, while labels in black indicate actual facts. The main stream of pieces goes from the epigenetic regulation hypothesis (top-left piece, no. 1) towards core symptoms (bottom-right piece, no. 12). Two-tone pieces (nos. 4, 6, and 11) stand for facts that appear downstream of two pieces coding for a hypothesis and another fact: in this theoretical framework, the disrupted architecture of sleep (no. 7) is caused by a poor degradation of serotonin (no. 3), which leads to aberrant neural paths (no. 11) that are built "offline" in the anticipation mode normally only relevant "online" (no. 10). For further details, see Beroule.
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F2
For the sake of simplicity, the way the above events are represented in the GP model can be displayed by an assembly of puzzle pieces (Figure 2). Blank situation, critical period of neurulation: The monoamine metabolism is durably adapted to the current fetal environment through MAOA downregulation (MAOA-in Figure 2).
Theoretical key functions of the molecular stimulation of type A monoamine oxidase (MAOA) in either initiation or alleviation of autism. At the top, several non-genetic factors share the property to significantly promote the expression of the MAOA gene. In the early gestation, an epigenetic downregulation of MAOA (MAOA:), which notably combines here with genetic variants of the catechol-O-methyl transferase (COMT) enzyme, may be inherited (blue arrow at the left-hand side) and/or favored/caused by MAOA enhancers (brown down arrow to the left). At the right-hand side, the series of smaller green arrows stand for a daily intake of MAOA inducer, which may bridge the gap between gestational and postnatal respective environments by reducing the metabolic imbalance of monoamines and consequently support behavioral re-education. At the bottom, a genetic variant (low-to-medium expression of COMT) and the classical epigenetic X-inactivation may hide the "MAOA:" mark, which is however silently carried towards the next human generation.
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F3
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.