Serotonin in utero-placental unit and genesis of postpartum depression
Grantee: MCG Research Institute, Inc.
Principal Investigator: Puttur Devi Prasad
Project Number: R40MC08967
Project Date: 2/1/2008
Final Report
Serotonin in utero-placental unit and genesis of postpartum depression Final Report (PDF)
Age group(s)
- Women/Maternal
Abstract
The primary goal of this project is to test our hypothesis on the role of serotonin in the utero-placental unit in the genesis of postpartum depression. Postpartum mood disorders (PMD) affect ~80% of women, resulting in major health consequences for mothers as well as infants, seriously jeopardizing the healthy development of MCH populations. There is a critical gap in the current understanding of the biochemical and genetic factors underlying the etiology of PMD. The studies proposed in this application are aimed at bridging this gap. Pharmacological evidence suggests that depression associated with PMD is due to reduced serotonergic neurotransmission and can be treated with SSRI drugs. Studies from our laboratory have shown that the serotonin transporter (SERT or 5-HT transporter) that clears serotonin (5-HT, 5-hydroxytryptamine) from the synaptic cleft in the brain is also expressed in the placenta where it helps in the clearing of serotonin, a potent vasoconstrictor, from the maternal blood in the intervillous space. Studies done in our laboratory have also shown that the cytokine interleukin-1 (IL-1) stimulates the expression of SERT. Based on our work and available literature evidence, we propose that there is a functional cross-talk between the placenta and uterine tissue as shown in Figure 1, which results in high expression of SERT in the placenta, low levels of serotonin in the intervillous space, and low levels of IL-1 in maternal circulation during pregnancy. The main tenet of our hypothesis is that the severance of the placenta-uterine crosstalk would result in increased IL-1 in the maternal circulation. The IL-1 would stimulate SERT expression in serotonergic neurons, which in turn would decrease serotonergic neurotransmission. Thus, according to this hypothesis, removal of placenta increases the risk for depression which would explain the widespread occurrence of postpartum blues, the milder form of PMD, in women. In Specific Aim 1, we propose to measure IL-1 longitudinally during the peripartum period to test the basic precept of our hypothesis i.e., there is an increase in circulating IL-1 in maternal blood postpartum. While most women experience postpartum blues, only a few suffer from the more severe forms of PMD. We propose that polymorphisms in the SERT gene are critical in the transition of postpartum blues to the severe forms of PMD. Several reports have provided evidence for a positive correlation between certain polymorphisms in the SERT gene and major depression. Such studies have not been done for postpartum depression. Proposed studies in Specific Aim 2 will examine the relevance of SERT gene polymorphisms to the etiology of PMD. Measuring changes in SERT expression in a woman's brain during the peripartum period is not possible. However, expression of SERT in leucocytes has frequently been used as a surrogate for the expression levels of the transporter in serotonergic neurons in the brain. In Specific Aim 3, we propose to investigate SERT expression in leucocytes collected at various times during the peripartum period and correlate it with plasma IL-1 levels and the nature of SERT allele. This will help confirm our hypothesis, viz., there is an increase in IL-1 level in maternal blood postpartum which in turn stimulates SERT expression in the brain leading to decreased serotonergic neurotransmission and hence depression in the mother. The proposed studies will greatly advance our understanding of the biochemical basis of postpartum depression and will have important implications in the diagnosis, treatment and management of PMD. PMD affects women worldwide; therefore the proposed studies have international relevance and address the Strategic Research Issue #IV of MCHB.<< Previous Next >>