Béroule Dominique G
LIMSI (Computer Sciences Laboratory for Mechanics and Engineering Sciences), CNRS, rue John Von Neumann, Campus Universitaire d'Orsay - Bâtiment 508, 91403, Orsay Cedex, France.
CRIIGEN Scientific Council (Committee for Independent Research and Information on Genetic Engineering), 42 rue de Lisbonne, 75008, Paris, France.
BMC Neurosci. 2018 Dec 17;19(1):80. doi: 10.1186/s12868-018-0477-1.
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.
In 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.
These 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.
环境因素可改变基因的表达，包括那些参与神经递质代谢的基因。考虑到单胺神经递质的控制作用，引导传播（GP）记忆模型可能有助于研究神经调节障碍对自闭症等发育障碍的影响。本文假设产前“单胺氧化酶A”酶的短暂过量会引发持续的表观遗传调控，从而导致突触单胺代谢失衡。当导入GP模型的“离线”编码周期时，随之产生的“血清素能噪声”会导致异常的记忆结构，这可能与自闭症症状相关。
在计算机实验中，单胺表征之间不同程度的解耦与受损的GP模块数量、无关连接的严重程度以及网络过度生长相关。分别假设两种类型的错误连接是自闭症特征的基础，即重复行为和感知过度敏感。除了计算建模，一个遗传谱系图展示了自闭症性别比例如何由药理学和表观遗传特征的组合产生。
这些结果表明，自闭症目前的上升趋势受到三种可能的生物掩盖来源的推动：（1）在睡眠期间，单胺的周期性变化可能会受到酶活性破坏的影响；（2）在受X染色体沉默和特定基因变异保护的“健康携带者”几代人中；（3）在生命早期，只要大脑发育利用的是在短暂酶过量及其持续的表观遗传调控重叠时产生的神经元池，并且只要B型单胺氧化酶对多巴胺没有显著影响。可以从这项研究中得出一种疾病改善疗法，该疗法涉及在几个月的临床试验中首先监测相关生物标志物。
