Neuroplasticidade na prole de ratas submetidas a ativação imune materna com lipopolisacarídeo

Abstract

The interaction between environmental and genetic factors is known as a potential risk factor for the development of neuropsychiatric disorders. Prenatal exposure to infections has been associated with the presentation of neurodevelopmental disorders such as autism spectrum disorder, as well as schizophrenia. The aim of this study was to evaluate behavioral, proteic and epigenetic changes in the offspring of females submitted to maternal immune activation (MIA) induced with lipopolysaccharide (LPS) at 16 th day of gestation (GD16).Female Wistar rats were treated intraperitoneally (i.p.) with 0.9% saline (1 ml/kg) or LPS (500 µg/kg) during GD16. To assess sickness behavior in the pregnant females, locomotor activity was recorded in the open field 2 hours after LPS administration, along with food intake and weight gain after 24hours. After the birth of the litters, behavioral tests were performed on the offspring to assess communication, social behavior, as well as recognition and spatial memory tests during adolescence. In adult offspring, locomotor activity, social behavior and the same memory tests performed in adolescent animals were assessed. After the behavioral tests, the prefrontal cortex (PFC) of the offspring was collected to quantify proteins related to neurodevelopment, synaptic plasticity, and social behavior through the western blot assay, and real-time PCR to evaluate the expression of factors involved in epigenetic modifications. In pregnant females, the administration of LPS decreased locomotion in the open field, food consumption and weight gain. In the offspring, no differences were found in the number of ultrasonic vocalizations (USV) in any of the analyzed groups. Regarding social behavior, the animals in the LPS group showed a decrease in the frequency and total time of social interactions in both females and males, and the changes persisted in the animals during adulthood. In adult offspring, a decrease in locomotor activity was also found in the open field. No differences were found in the performance of the offspring in any of the memory tests in both the adolescent and adult animals. In adolescent animals from the LPS group, an increase in the expression of the oxytocin receptor (OTR) was found in the PFC of females and males. A decrease in glucocorticoid receptor (GR) and synaptophysin expression was also found only in the PFC of males, but not in females. An increase in the expression of the Line1 Retroelement and the RE- 1 Silencing Transcription Factor (Rest) was also found in the PFC of adolescent males, as well as an increase in the enzymes DNA methyltransferases (DNMTs) and ten-eleven translocation (TETs) in the PFC of males and female LPS, involved in DNA methylation and demethylation.

Our results demonstrate that the administration of LPS during DG16 was able to generate sex- dependent molecular changes in the prefrontal cortex of the offspring, which could be involved in the behavioral changes resulting from MIA.