News and ReviewsRole of neurotrophins in pregnancy and offspring brain development
Introduction
Neurotrophins are a family of growth factors which play a key role in the differentiation, growth and survival of neuronal as well as non-neuronal cells (Huang and Reichardt, 2001). They include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) (Lee et al., 2001). NGF is expressed in both neuronal and non-neuronal cells of the central and peripheral nervous system (Sofroniew et al., 2001). Various regions of the brain such as hippocampus, cortex and pituitary gland are suggested to have the highest NGF expression (Aloe et al., 2012; West et al., 2014) while BDNF is expressed in the hippocampus, cortex, cerebellum and amygdala (Adachi et al., 2014).
The biological functions of neurotrophins are mediated by high affinity tyrosine kinase receptors (trk) which play a major role in the biological functions of neurotrophic target cells and low affinity receptor p75 (Hempstead, 2002). NGF exerts its effects by binding to the trkA receptor located on the cell surface (Huang and Reichardt, 2003; Molloy et al., 2011; Vera et al., 2014) which activates the cytosolic/endosomal pathways such as PI3K, phospholipase C and ras-mitogen activated protein kinase (MAPK) (Klesse and Parada, 1999; Reichardt, 2006). BDNF binds to its high affinity receptor trkB as well as to p75NTR with low affinity (Barbacid, 1994). NT-3 binds with a greater affinity to trkC and lesser affinity to trkB (Razavi et al., 2015) whereas NT-4 binds with trkB (Bothwell, 2014).
During the past few years various studies have demonstrated the involvement of neurotrophins in various processes during pregnancy (Bienertova-Vasku et al., 2013; Frank et al., 2014). In the mother, neurotrophins are involved in regulating implantation, maternal immunity and modulating vascular growth (Toti et al., 2006). Neurotrophins like NGF and BDNF play an important role in placental development and maturation (Kawamura et al., 2007; D'Angelo et al., 2020). Neurotrophins are also termed as “angioneurins” as they regulate angiogenesis (Zacchigna et al., 2008). During embryogenesis, BDNF and NT-3 play an important role in angiogenesis and vessel stabilization (Kermani and Hempstead, 2007). Angiogenesis may be directly induced by NGF via its receptor or indirectly through vascular endothelial growth factor, an angiogenic factor (Nico et al., 2008). Studies from our group have demonstrated altered levels of neurotrophins like NGF and BDNF in preeclampsia (V. A. D’Souza et al., 2014b, Sahay et al., 2015).
Neurotrophins may influence angiogenic processes through various neuropeptides. This may have implications in pregnancy specific disorders such as preeclampsia which is characterized by impaired angiogenesis and increased blood pressure. Neuropeptides such as angiotensin-II, has been shown to influence angiogenesis along with its receptors ang II type 1 receptor (AT1R) and type 2 receptor (AT2R) and regulates blood pressure (Gallo-Payet et al., 2011; Guimond and Gallo-Payet, 2012). We have earlier demonstrated higher concentrations of angiotensin II type 1 receptor auto-antibodies (AT1R-AA), which are auto-antibodies against angiotensin II receptor type 1 (AT1R) in women with preeclampsia (Sahay et al., 2014). Another neuropeptide, Neuropeptide Y (NPY) has also been reported to be involved in elevating the blood pressure (Tan et al., 2018). A recent study reports reduced expression of NPY receptor in women with preeclampsia which may be associated with abnormalities of placental angiogenesis (Klinjampa and Sitticharoon, 2019).
Neurotrophins like BDNF cross the utero-placental barrier to reach the fetal brain (Kodomari et al., 2009). They are involved in prenatal and postnatal development of the brain and have neuroprotective action (Nikolaou et al., 2006). Neurotrophins have been shown to modulate the expression of neuropeptides like neuropeptide W in neuronal cells via the PI3K/Akt pathway (Wang et al., 2017). Both neurotrophins and neuropeptides have been shown to play an important role in influencing synaptic properties in the developing and the mature nervous system (Zagrebelsky and Korte, 2014; Catalani et al., 2017).
Various intrauterine factors such as maternal nutrition during pregnancy influence fetal brain plasticity and neurodevelopment (Lindsay et al., 2019). Our studies in rats have demonstrated that a combined supplementation of n-3 poly unsaturated fatty acids (PUFA) and vitamin B12 improve the concentrations of neurotrophins like BDNF and NGF in the brain leading to improved neurovascular function and brain development (Rathod et al., 2015; Rathod et al., 2016). Brain neurotrophins are also influenced by a maternal diet with high levels of folate and low vitamin B12 resulting in lowered cognitive function in the offspring (Sable et al., 2011; Sable et al., 2012). In another study, mice fed a high fat diet had reduced expression of BDNF, NGF and NT-4/5 in the offspring brain leading to impaired neurogenesis and synaptic plasticity (Bae-Gartz et al., 2019). Rats fed a high fat diet are reported to reduce NPY 1 receptor and BDNF in the hippocampus and frontal cortex increasing the vulnerability for anxiety-like behaviour (Sharma et al., 2012). A study in rats also demonstrates that omega-3 deficient diet decreases NPY 1 receptor and BDNF in the hypothalamus and hippocampus of male offspring rats (Bhatia et al., 2011). However, these limited studies in animals report the influence of maternal diet either on the concentrations of neurotrophins or neuropeptides in the offspring brain. To the best of our knowledge there are no studies which have examined the role of maternal nutrition in regulating neurotrophins and neuropeptides to influence pregnancy outcome and offspring brain development. It is likely that during pregnancy, maternal nutrition influences the levels and expression of neurotrophins and neuropeptides thereby regulating angiogenesis and influencing placental and brain development (Fig. 1).
The present review summarizes the studies on neurotrophins in pregnancy and brain development and discusses the possible mechanism through which maternal nutrition can influence neurotrophins and neuropeptides to influence pregnancy outcome and offspring brain development.
Section snippets
Role of neurotrophins during pregnancy
Implantation of the embryo marks the initiation of pregnancy, wherein the embryo adheres to the endometrial surface of the uterus (Kim and Kim, 2017). Neurotrophins like BDNF and neurotrophin-3 have been suggested to be involved during the preimplantation stage as well as early embryonic development (Kawamura et al., 2007; Bernd, 2008). Reduced serum BDNF levels have been reported early in an IVF cycle in women having ectopic pregnancy or spontaneous abortion as compared to women who gave live
Neurotrophins and pregnancy complications
Alterations in the levels of neurotrophins leads to placental pathologies resulting in various pregnancy complications like preeclampsia, gestational diabetes mellitus (GDM), preterm births, and intrauterine growth restriction (Mayeur et al., 2010; Dhobale et al., 2013; Dhobale, 2014; Sahay et al., 2015; Briana et al., 2018). Table 1 and Table 2 summarize various human studies examining NGF and BDNF in these pregnancy complications. These studies demonstrate that a balanced expression of
Role of neuropeptides in pregnancy
During pregnancy, neuropeptides like melatonin, urocortin, oxytocin and serotonin play an important role in processes like placental development, appetite regulation, regulation of hormones like estrogen and in the process of parturition (Vitale et al., 2016; Kim et al., 2017; Napso et al., 2018; Hudon Thibeault et al., 2019). Although there are many neuropeptides as discussed above, which are involved in various processes throughout pregnancy, the section below focuses on kisspeptins and
Role of neurotrophins during brain development
Differentiation of the neural progenitor cells in the third week of gestation begins the brain development of the fetus (Stiles and Jernigan, 2010). Processes of neuronal growth and differentiation in peripheral and central nervous system of a developing fetus involve neurotrophins like BDNF and NGF (Tometten et al., 2005; Garces et al., 2014; Bathina and Das, 2015). BDNF has been suggested to be the key regulator of the neural circuit development in the central nervous system, where it is
Neuropeptide Y and brain development
NPY is one of the most abundant neuropeptides in the central and peripheral nervous system and is involved in various functions in the brain including neurogenesis, neuroprotection and neuroinflammation (Malva et al., 2012). These are widely distributed in brain regions such as hippocampus, amygdala and the basal forebrain responsible for learning and memory processes (Borbély et al., 2013). It is a neurotransmitter whose proliferative effects are mediated via G protein-coupled receptors - Y1R,
Preeclampsia and offspring brain neurodevelopment
Offspring exposed to hypertensive disorders of pregnancy like preeclampsia have increased risk of developing neurodevelopmental disorders like attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) (Nomura et al., 2017; Maher et al., 2018). Children with ASD are twice as likely to have been exposed to preeclampsia in utero as compared to controls indicating that systemic inflammation, faulty placentation, nutrient transfer restriction and oxidative stress influence
Possible mechanism through which maternal nutrition influences neurotrophins and neuropeptides thereby regulating offspring brain development and function
Maternal nutritional status plays a major role in determining pregnancy outcome and fetal well being (Morrison and Regnault, 2016). Imbalanced maternal nutrition is suggested to have an association with pregnancy complications like preeclampsia (Baker et al., 2018). Micronutrients such as vitamin B12 and folate are important regulators of the one carbon cycle and influence pregnancy outcome resulting in intrauterine programming of diseases in the offspring in later life (Yajnik and Deshmukh,
Conclusion
Neurotrophins are involved in placental and fetal brain development. Further, their expression is altered in complications of pregnancy such as preeclampsia. Maternal nutrition affects the levels and expression of these neurotrophins which may regulate fetal brain growth and development possibly through alterations in the concentrations of neuropeptides. In order to better understand the role of maternal nutrition on plasma and placental neurotrophins our group has initiated a study (REVAMP
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgement
The authors thank the Indian Council of Medical Research for funding the REVAMP study (5/7/1069/13-RCH). Author AS thanks the Indian Council of Medical Research (ICMR), Government of India for providing her the ‘RA fellowship’ (RBMH/FW/2019/17).
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