Fig. 4

Theoretical model to link prenatal stress, reelin and PFC cognitive impairment. This model, which unifies molecular, cellular and clinical organizational criteria, proposes that PNS induces methylation of the reelin promoter, resulting in the down-expression of reelin in synthesizing cortical neurons, the effects of which begin to manifest themselves in the prenatal development and are maintained during consequent developmental stages to adulthood. In prenatal stages, down-expression of reelin produces alterations in neuronal cytoskeleton dynamics that result in deviances from normal neuronal architecture of the PFC, such as altered positioning of neurons, reduction of dendritic complexity, and reduction of the number of GABAergic neurons, resulting in altered developmental neuronal connectivity. Due to the stability of epigenetic alterations, down-expression of reelin continues during postnatal stages to adulthood, where it is manifested as an impairment of activity-dependent synaptic plasticity. These structural and functional alterations modify neuronal connectivity, especially in GABAergic interneurons, leading to altered functional connectivity in the PFC expressed as decreased oscillatory activity, especially at the gamma-frequency band. Given that functional connectivity is required for the implementation of executive function by the PFC, these changes can manifest themselves as cognitive and behavioral impairments dependent on the PFC. Finally, this model does not exclude other candidate genes that may also be affected by PNS and impact on the symptomatology of schizophrenia