Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Abstract

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

The role of IL-6 in neurodevelopment after prenatal stress

“…Indeed, our group has previously associated behavioral inhibition after prenatal stress with alterations in GABAergic maturation (Lussier and Stevens, 2016). Other reports suggest that inter-related aspects of GABAergic development—epigenetic changes in GABAergic genes—and their correction, are also correlated with behavioral changes after prenatal stress (Matrisciano et al, 2013; Negron-Oyarzo et al, 2016). …”

Genetics and Epigenetics of Schizophrenia

“…Some authors have found methylation differences in different genes, including COMT, RELN, and in some other genes implicated in dopaminergic, serotoninergic, γ-aminobutyric acid (GABA)ergic, and glutamatergic pathways [103]. It has been proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairments observed in SCZ [104]. Reelin (RELN) is involved in cortical neural connectivity and synaptic plasticity.…”

Relationships of rs7341475 polymorphism and DNA methylation in the reelin gene with schizophrenia symptoms

“…от присоединения метильной группы к цитозину преимущественно в составе динуклеотидов цитозин-гуанин (CpG). На этом основании предполагается, что гиперметилирование в промоторе RELN, обусловливающее снижение транскрипции гена, может быть важным звеном в каскаде событий, ведущих от пренатального стресса к нарушениям развития нервной системы, особенно строения префронтальной коры, и далее к изменениям процессов обработки информации и манифестации шизофрении [13]. Однако результаты изучения у больных метилирования промотора RELN противоречивы [14].…”