Impaired experience-dependent maternal care in presynaptic active zone protein CAST-deficient dams

Abstract

Although sociological studies affirm the importance of parental care in the survival of offspring, maltreatment-including child neglect-remains prevalent in many countries. While child neglect is well known to affect child development, the causes of maternal neglect are poorly understood. Here, we found that female mice with a deletion mutation of CAST (a presynaptic release-machinery protein) showed significantly reduced weaning rate when primiparous and a recovered rate when multiparous. Indeed, when nurturing, primiparous and nulliparous CAST knock out (KO) mice exhibited less crouching time than control mice and moved greater distances. contrary to expectations, plasma oxytocin (OXT) was not significantly reduced in CAST KO mice even though terminals of magnocellular neurons in the posterior pituitary expressed CAST. We further found that compared with control mice, CAST KO mice drank significantly less water when nurturing and had a greater preference for sucrose during pregnancy. We suggest that deficiency in presynaptic release-machinery protein impairs the facilitation of some maternal behaviours, which can be compensated for by experience and learning.Parental care is essential for the survival of mammalian offspring and influences their adult lives mentally and physically. Naturally, both parents have responsibilities from nest building to feeding, but because they lactate, the primary responsibility for parental care falls to mothers 1 . As nursing is essential for mammalian survival, the basic neural mechanisms underlying maternal care are likely conserved throughout the mammalian evolutionary tree. Therefore, studying these neural mechanisms in non-human mammalian models such as gene-transgenic mice 2 can help us understand human maternal care and prevent neglect. In rodents, maternal behaviours such as nest building, gathering pups together in the nest, keeping them warm, and nursing are critical for pup survival.Complex maternal behaviours require highly motivated and flexible neural systems and have frequently been associated the neuropeptide oxytocin (OXT), which is secreted in both the periphery and the brain 2-5 . Indeed, considerable evidence indicates that OXT promotes maternal behaviour, while OXT deficiency (OXT KO in rats) results in impaired milk ejection without obvious defects in parturition 3 . Similarly, a null mutation of the OXT receptor in mice led to defects in lactation and maternal behaviour 6,7 . Additionally, mice deficient in CD38 (a transmembrane glycoprotein with ADP-ribosyl cyclase activity) also showed defects in maternal behaviour correlating with the reduction of plasma OXT levels 8 . Therefore, OXT and its receptor system are essential for the regulation of maternal behaviour. However, OXT is just one of the many critical players; complex maternal behaviours are also regulated by other neuromodulators including dopamine, serotonin, norepinephrine, and corticotropin-releasing factor, which have been associated with maternal motivation and stress-induced anti-maternal be...

Experience-Regulated Neuronal Signaling in Maternal Behavior

“…Experience-dependent maternal behavior can be regulated by proteins that act at the presynaptic active zone of the neuron. The presynaptic active zone protein CAST, which is a presynaptic release machinery-protein that acts as an anchor for neurotransmitters and neuromodulators was examined for its role in maternal behavior, using CAST knockout primiparous and multiparous females (Hagiwara et al, 2020 ). Primiparous CAST knockout females showed a decrease in crouching and nest building which were significantly improved with their second litter.…”