Offline encoding impaired by epigenetic regulations of monoamines in the guided propagation model of autism

Abstract

Background Environmental factors can modify the expression of genes, including those involved in the metabolism of neurotransmitters. Accounting for a control role of monoamine neurotransmitters, the guided propagation (GP) memory model may contribute to investigate the consequences of neuromodulation impairments on development disorders such as autism. A prenatal transient excess of ‘monoamine oxidase A’ enzyme is assumed here to trigger persistent epigenetic regulations that would induce imbalanced metabolisms of synaptic monoamines. When imported into the ‘offline’ encoding cycles of a GP model, the consequent ‘serotoninergic noise’ leads to aberrant memory structures that can be linked with autism symptoms.ResultsIn computer experiments, different levels of uncoupling between representations of monoamines correlate with the amount of impaired GP modules, the severity of irrelevant connections, as well as network overgrowth. Two types of faulty connections are respectively assumed to underlie autism traits, namely repetitive behavior and perceptual oversensitivity. Besides computational modelling, a genetic family-tree shows how the autism sex-ratio can result from combinations of pharmacological and epigenetic features.ConclusionsThese results suggest that the current rise of autism is favored by three possible sources of biological masking: (1) during sleep, when cyclic variations of monoamines may undergo disrupted enzymatic activities; (2) across generations of ‘healthy carriers’ protected by the X-chromosome silencing and a specific genetic variant; (3) early in life, as long as the brain development draws on pools of neurons born when the transient enzymatic excess and its persistent epigenetic regulation overlapped, and as long as the B type of monoamine oxidase does not significantly impact dopamine. A disease-modifying therapy can be derived from this study, which involves relevant biomarkers to be first monitored over several months of clinical trial.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0477-1) contains supplementary material, which is available to authorized users.

Paradoxical Effects of a Cytokine and an Anticonvulsant Strengthen the Epigenetic/Enzymatic Avenue for Autism Research

“…Moreover, the male full prevalence suggests the mediation of at least one protein whose gene is carried by the X chromosome (i.e., MAOA), besides sex-specific loci present in the SERT gene (Weiss et al, 2005 ). In addition, the surprising time delay of positive effects following SERT inhibition aimed at alleviating ASD symptoms in Ala56 mice (Robson et al, 2018 ) can be explained by the time-consuming neural migration necessary for new neural structures to be encoded and consolidated under well-regulated MAOA (Béroule, 2018 ).…”

“…The relatively poor degradation of 5-HT assumed here would only initiate visible effects in the early childhood, when the third metabolizer (MAOB) is mature enough to supply the baseline catabolism of DA. This enzymatic reading provides an explanation for the regressive feature of ASD, while the X-inactivation and COMT polymorphism (low to high expressions) can together account for the male prevalence (Béroule, 2018(Béroule, , 2019. Consequent structural deficits are represented by a GP network in which the local 5ht parameters decrease slower than Ne across offline encoding, inducing either aberrant or lacking memory pathways (Béroule, 2016).…”

“…As a matter of fact, up to 40% of women exposed to VPA during pregnancy had given birth to children with intellectual disabilities and autism. Meanwhile, on the research front, a computational model of autism (Béroule, 2018 ) predicted that besides its classical anticonvulsant properties, VPA could serve as an autism-modifying drug for its capacity to promote the type A monoamine oxidase (MAOA) genetic expression (Gupta et al, 2015 ). In 2015–2016, a preliminary case study concerned the daily intake of a VPA-based anticonvulsant, monitored over 12 months in an 11-year-old child with severe autism and epileptic signs.…”

The “Connectivome Theory”: A New Model to Understand Autism Spectrum Disorders

“…During this phase, epigenetic regulation allows the brain to adapt to the specific environment in which the individual is growing, even during the prenatal stage. Recent evidence suggests that microglia plays an important role in responding to pre- and postnatal environmental stimuli through the epigenetic interface, modifying gene expression and thus acting as an effector of synaptic plasticity ( 20 ). A sophisticated crosstalk between the enteral nervous system and intestinal microbiome in the gut appears to be particularly critical for various facets of CNS physiology, including the development of microglia and its functions ( 21 ).…”

Linking autism to an imbalanced catabolism of synaptic monoamines

“…In addition, the late occurrence of autistic symptoms may be consistent with the rising of the MAOB enzyme that degrades another monoamine (dopamine), but only significantly around two years after birth. The consequent long-term imbalance of synaptic monoamines is assumed here to impact the architecture of sleep and learning [1], inducing a range of developmental problems. This theory is drawn on Guided Propagation Networks (GPNs), the computer simulations of which show the growth of aberrant structures when modulation parameters akin to monoamines do not satisfy inner learning constraints.…”