Receptor for advanced glycation end-products and child neglect in mice: A possible link to postpartum depression

Abstract

The receptor for advanced glycation end-products (RAGE), a pattern recognition molecule, has a role in the remodeling of vascular endothelial cells mainly in lungs, kidney and brain under pathological conditions. We recently discovered that RAGE binds oxytocin (OT) and transports it to the brain from circulation on neurovascular endothelial cells. We produced knockout mice of the mouse homologue of the human RAGE gene, Ager, designated RAGE KO mice. In RAGE KO mice, while hyperactivity has been reported in male mice, maternal behavior was impaired in female mice. After an additional stress, deficits in pup care were observed in RAGE KO mother mice. This resulted in pup death within 1-2 days, suggesting that RAGE plays a critical role during the postpartum period. Thus, RAGE seems to be important in the manifestation of normal maternal behavior in dams. In this review, we summarize the significance of brain OT transport by RAGE and propose that RAGE-dependent OT can dampen stress signals during pregnancy, delivery and early postpartum periods. To the best of our knowledge, there have been no previous articles on these RAGE-dependent results. Based on these results in mice, we discuss a potential critical role of RAGE in emotion swings at the puerperium (peripartum) and postpartum periods in women.

Keywords: Maternal behavior; Oxytocin; Peripartum; Postpartum; Puerperium; RAGE; Stress.

Fig. 1

Effect of stress on mice dam behavior. Stress application (cage bedding changing) on the day before delivery resulted in 80% of pups' death in RAGE KO dams but not in WT. Stress on PPD3 (new environment/restraining) led to anxiety and less pup care only in RAGE KO dams.

Fig. 2

Maternal retrieval behavior of dams at postpartum day (PPD) 3 with pups placed in the four corners of the open field. Scheme of experiments in the open field. Pups were placed at each corner on PPD 3. Scores from 0 to 4 are shown: 0, no retrieval; 1, one pup was retrieved to one of the other corners; 2, two pups were retrieved to two different corners; 3, two pups were retrieved to the same corner; and 4, three pups were retrieved to one corner to join the fourth pup and form a complete nest [40]. Lower graphs indicate maternal scores of wild-type (BL6) or RAGE KO dams at PPD 3. RAGE, receptor for advanced glycation end-products; KO, knockout.

Fig. 3

Scheme depicting factors involved in inducing or inhibiting maternal behavior in wild-type dams at postpartum day 3. (A) RAGE-dependent oxytocin (OT) recruitment to the brain and facilitation of OT release to the brain by the reproductive processes, including pregnancy, parturition, and lactation, which increase brain (central) OT levels. These OT levels induce maternal behavior. Additional restraint or stressful social stimuli (exogenous stress) activates stress responses (hypothalamus-pituitary-adrenal axis) in mice. These stress signals are also activated by reproductive processes (endogenous stress). However, brain OT levels may be able to reduce (antagonize) the stress response. RAGE, receptor for advanced glycation end-products. (B) Stress inputs from additional exogenous stress and reproductive processes are at the same level as for wild-type dams. Because there is no contribution of RAGE to central (brain) OT levels, activation of stress responses is not suppressed. Therefore, signals that inhibit maternal behavior overcome induction signaling from brain OT levels. RAGE, receptor for advanced glycation end-products; KO, knockout; OT, oxytocin.

Fig. 4

Scheme depicting two hits leading to maternal depression. Dams with reproductive stress conditions (basal condition) will get the first (no RAGE-dependent OT recruitment) and second (exogenous social or restraint stress) hits, resulting in maternal depression. RAGE, receptor for advanced glycation end-products; OT, oxytocin.