Maternal exposure to swainsonine impaired the early postnatal development of mouse dentate gyrus of offspring
Introduction
Locoweeds, from Oxytropis and Astragalus, are a great threat to grass farming in the livestock industry (Lu et al., 2014a; Wu et al., 2014). Swainsonine (SW) is the main toxin in locoweeds (Obeidat et al., 2005; Yu et al., 2010). Studies have shown that SW can inhibit α-mannosidase and finally result in the formation of vacuoles in different kinds of cells (Armien et al., 2007; Wang et al., 2013). SW-poisoning animals do have clinical symptoms of nervous system damage such as mentally depressed, drowsy and ataxia (Armien et al., 2011; Dantas et al., 2007; Driemeier et al., 2000; Wu et al., 2014). Once the poisoned animals stop feeding on locoweeds, the structure and function of cells in most systems and organs generally recover within a few days to several weeks (Armien et al., 2011; Dantas et al., 2007; Wu et al., 2014). However, the nervous system damage is not easy to repair, and even lead to permanent neurological disorders. These imply that the nervous system is more sensitive to SW than other systems.
In rodents, the developing central nervous system has a critical period called brain growth spurt--from the end of pregnancy to the first 2–3 weeks after birth; in humans, the corresponding period begins at the final trimester of pregnancy and lasts 2 years after birth (Byrnes et al., 2001). During this time, the brain exhibits rapidly substantial neurogenes and has a high degree of plasticity, laying foundations for the normal structure and function of the brain. The hippocampal dentate gyrus (DG) is one of regions where neurogenesis occurs during development and continues, at a slower rate, into adulthood. Hippocampus is primarily composed of DG, the cornus ammonis (CA) and the subiculum, and critical for certain forms of learning and memory (Squire and Zola-Morgan, 1991). It has been confirmed that a positive correlation between neurogenesis in DG and the performance of the animal on behavioral tasks (Kempermann et al., 1997; van Praag et al., 1999).
DG development begins from around gestation day (GD) 15 and lasts until the postnatal day (PND) 14-21, which is accomplished by multiple spatiotemporally regulated developmental processes involving proliferation, migration, differentiation, and morphological change of neural stem cells (NSCs) (Altman and Bayer, 1990a, b; Li and Pleasure, 2005). NSCs including radial glial cells (RGCs) and intermediate neural progenitors (INPs) migrate toward the hilus of DG and form a proliferative zone, called the subgranular zone (SGZ), at the border between the hilus and the granular cell layer (GCL) in the second postnatal week (Li et al., 2009; Li and Pleasure, 2005), and neurogenesis in the SGZ contributes to be persistent throughout life. RGCs produce INPs and further differentiate into granule cells (GCs) that are integrated into the GCL. However, only some newborn GCs can migrate into the normal position of the GCL to finish the functional demand (Dupret et al., 2007; Kee et al., 2007). During the process, reelin signaling participates in the final destination of GCs (Brunne et al., 2013). A great deal of neuropathological defects that cause high cognitive dysfunction are accompanied by abnormal hippocampal neurogenesis and plasticity (Xu et al., 2015). Seizures have effects on the development of hippocampal neurogenesis and irregular hilar basal dendrites (Hattiangady and Shetty, 2010; Jessberger et al., 2007). Normally, GCs develop dendrites towards the molecular layer (ML) of DG and send axons through the hilus. In contrast, dendrites from seizure-induced GCs appear to grow the hilus rather than the ML. In addition, results have demonstrated that factors that interfere with neuronal production (eg, after birth or adult) may have serious implications on hippocampus-dependent function (Kempermann and Gage, 2002; Young et al., 1999). Therefore, neurogenesis in the DG plays a key role in the normal of structure and function of the hippocampus.
The study has shown that SW can cause apoptosis of dopaminergic neurons in the midbrain (Li et al., 2012). Treatment with SW can affect the growth of rat neuronal processes, the expression of Golgi mannosidase II and lead to neuronal apoptosis (Lu et al., 2013, 2014b). In addition, our previous study found that SW significantly inhibited adult neurogenesis in hippocampus and affected spatial learning and memory in mice (Wang et al., 2015). Here, at the GD 10, dams were exposed to SW and continued until the PND 21 to investigate the effects of SW on the neurogenesis of DG. Our results showed that SW exposure impaired proliferation of RGCs and INPs and reduced the number of newborn cells in DG on offspring at PND 8. Using postnatal in vivo electroporation and western blot, we found that SW affected dendritogenesis of GCs and reduced the expression level of spinophilin in neonatal hippocampus. Interestingly, the number of NeuN+ and Reelin+ cells in hilus significantly increased, suggesting the migration defect of newborn neurons. In addition, by western blot analysis, we found the relative expression level of NeuN with treatment of 8.4 mg/kg SW obviously decreased in the whole neonatal hippocampus, suggesting that SW did disrupt the development of hippocampus. These results indicated that exposure of dams to swainsonine affected early development of dentate gyrus on offspring.
Section snippets
Chemical reagents and antibodies
Swainsonine (SW, purity > 99.8%), propidium iodide (PI) and 5′-Bromo-2′-deoxyuridine (BrdU) were from Sigma. 4′, 6′-diamidino-2-phenylindole (DAPI) was purchased from Abcam. For immunofluorescence staining, the primary antibodies used in the present study were as follows: rabbit anti-BLBP (Millipore, ABN14, 1:500), rat anti-BrdU (Santa Cruz Biotechnology, sc-56258 1:500), rabbit anti-GFP (Thermo Fisher Scientific, G10362, 1:200), rabbit anti-prox1 (Millipore, AB5475, 1:1000), mouse anti-NeuN
SW exposure did not affect the body weight of dams as well as the body weight and brain of their offspring
No significant difference was found in the body weight of dams between the control group and the SW-treated groups (Fig. 1a). Brain weight (Fig. 1b), body weight (Fig. 1c) and the ratio of body weight to brain weight of the offspring mice (Fig. 1d) did not show significant difference between the control group and the SW-treated groups.
SW exposure impaired the early development of postnatal DG
It is well known that as the RGCs proliferate to expand the DG, they produce INPs and later migrate to the hilus of the DG to give rise to the prospero homeobox
Discussion
SW is the main toxic ingredient in locoweeds, causing serious loco disease (“locoism” or “pea struck”) characterized by weight loss, altered behavior, depression, abortion, birth defects, and even death (Stegelmeier et al., 1999). SW has a molecular weight of 173, smaller than that of pathogens so that it can pass placental barrier freely to embryos. Here, we exposed SW to dams to study neurotoxicity on DG of their offspring, including cell proliferation and development during the early
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgments
The work was supported by National Natural Science Foundation of China (No. 31572477 to S.Z.), Resource-based Industry Key Technology Project of Shaanxi Province, China (No. 2016KTCL02-19 to S.Z.), the Natural Science Foundation of Shaanxi Province, China (No. 2018JM3041 to X.Z.) and the Shenzhen Basic Research (Layout of Disciplines) Project Fund, China (JCYJ20170413154810633 to Y.W.).
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