Figure 6

Hypothetical model of the synaptic mechanism regulating Aβ production and the link to aberrant brain growth and connectivity in autism. The development of living organisms parallels to a so-called physiological ‘intrinsic developmental stress’, which is associated to massive internal changes during morphogenesis, and thus contributes to the time window of vulnerability to the environment. Development and severity of ASD are likely to arise from complex interactions between pre-existing genetic vulnerability/ies in these children, the exposure to noxious environmental factors, and the timing of the stressful event(s); given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.^{2, 3} Glial activation and neuroinflammation seem to persist during adulthood in autism, and early brain overgrowth in autism could be a consequence of an over-activation of neural proliferation in a trial to compensate the cellular loss induced by environmental stress/ors, triggering precipitous/uncontrolled migration and misdistribution of neurons among different brain areas. Our model proposed that aberrant epigenetic regulation may lead to increased density of NMDA receptors and, therefore, to increased Ca⁺² entry and stimulation of ERK-dependent α-secretase activity. The decrease in mitochondrial enzymatic activity together with the downregulation of PSEN2 at the ER may represent a compensatory mechanism to reduce the Ca²⁺ overload-induced apoptosis. PSEN2 downregulation may diminish the interaction between ER and mitochondria, reducing its Ca⁺² uptake. In turn, mitochondrial mass would increase most likely to maintain the cellular ATP levels. Higher levels of sAPPα would activate the PI3K/Akt/mTOR pathway resulting in proliferation, aberrant brain growth, and disruption of synaptic plasticity and connectome