Maternal separation induces changes in TREK-1 and 5HT1A expression in brain areas involved in the stress response in a sex-dependent way.

Depression is a prevalent disease in modern society, and has been linked to stressful events at early ages. Women are more susceptible to depression, and the neural basis for this are still under investigation. Serotonin is known to be involved in depression, and a decrease in 5HT1A expression is observed on temporal and cortical areas in both men and women with depression. As knockout animals for TREK-1 are resilient to depression, this channel has emerged as a new potential pharmacological target for depression treatment. In this study, maternal separation (MS) was used to emulate early-life stress, and evaluate behaviour, as well as TREK-1 and 5HT1A expression in the brain using immunohistochemistry. In juvenile females, 5HT1A reduction coupled to increased TREK-1 in the dentate gyrus (DG) was associated with behavioural despair, as well as increased TREK-1 expression in basolateral amygdala (BLA) and prelimbic cortex (PL). In juvenile males, MS induced an increase in 5HT1A in the BLA, and in TREK-1 in the PL, while no behavioural despair was observed. Anhedonia and anxiety-like behaviour were not induced by MS. We conclude stress-induced increase in TREK-1 in PL and GD is associated to depression, while 5HT1A changes coupled to TREK-1 changes may be necessary to induce depression, with females being more vulnerable to MS effects than males. Thus, TREK-1 and 5HT1A may be potential pharmacological targets for antidepressants development.

Maternal exposure to fluoxetine during gestation and lactation induces long lasting changes in the DNA methylation profile of offspring's brain and affects the social interaction of rat.

Fluoxetine (FLX) is an antidepressant from the selective serotonin reuptake inhibitor class that has largely been used for the treatment of depression in pregnancy. However, increasing evidences have indicated the potential of early maternal exposure to FLX to induce molecular and neuro functional effects on the offspring. In the present study we evaluated possible long lasting impacts of the maternal exposure to FLX during gestation and lactation. Female Wistar rats were gavaged with 5 mg/kg of FLX during the period that comprehends the first day of pregnancy (PD0) and the last day of lactation (LD21) (Group FLX). Control group (CTL) received a proportional volume of water. On the postnatal day 75 (PND75), male rats were euthanized and hippocampus, cortex, hypothalamus, and periaqueductal gray area (PAG) were removed. Global DNA methylation was quantified using a high-throughput ELISA-based method. In order to address neuro functional changes animals (PND75) were evaluated in the elevated plus maze and social interaction tests as well as submitted to repeated restraint stress. An increase in the global DNA methylation profile of hippocampus (p = 0.0399) was associated with the early exposure to FLX, whereas no significant change was observed in the hypothalamus (p = 0.6556), cortex (p = 0.9402) or PAG (p = 0.3822). Furthermore, early exposure to FLX was also associated with a reduction in the social interaction time (p = 0.0084) and to a decreased in the plasma corticosterone level when animals were submitted to the restraint stress (p < 0.0001). No significant change in the elevated plus maze test was associated with the early exposure to FLX. In summary, our data demonstrate that maternal exposure to FLX during gestation and lactation results in a long lasting impact on the DNA methylation of hippocampus, and affects the social behavior and the corticosterone response to stress.