Abstract
BackgroundEnvironmental 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.
Highlights
Environmental factors can modify the expression of genes, including those involved in the metabolism of neurotransmitters
Neuromodulators possibly unbalanced by epigenetic regulations Monoamines under influence Mostly focused on synapses and neurons, genetic investigations have concerned the controlled networking of neurons by neuromodulators, including serotonin (5-HT) for its recognized contribution to the brain development [7]
In the blood of autistic patients, high 5-HT levels can be attributed to its increased synthesis by tryptophan hydroxylase, enhanced uptake into platelets through transporter, or decreased metabolism by the monoamine oxidase type A (MAOA) enzyme [8]
Summary
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. Neuromodulators possibly unbalanced by epigenetic regulations Monoamines under influence Mostly focused on synapses and neurons, genetic investigations have concerned the controlled networking of neurons by neuromodulators, including serotonin (5-HT) for its recognized contribution to the brain development [7]. In the blood of autistic patients, high 5-HT levels can be attributed to its increased synthesis by tryptophan hydroxylase, enhanced uptake into platelets through transporter, or decreased metabolism by the monoamine oxidase type A (MAOA) enzyme [8]. MAOB, the other type of monoamine oxidase, may be involved in ASD, since its brain concentrations, barely detectable at birth, reach a high at around 2 years of age [10], when autism symptoms start being revealed
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