MicroRNAs are heterochronic molecules important during brain development, which could be altered by gestational diabetes mellitus (GDM). To explore these molecules in maternal serum, we performed an RT-qPCR analysis. Our results revealed the heterochronic character of some neural development-related microRNA in serum samples of pregnant women. In relation to the first trimester, higher levels of miR-183-5p, -200b-3p, and -125-5p in the second trimester, and higher levels of miR-137 in the third trimester, were found. Furthermore, an insult such as GDM led to higher levels of miR-183-5p, -200b-3p, -125-5p, and -1290 relative to the control in the first trimester, which might be related to changes in neurogenesis and cell proliferation. An in silico analysis suggested that increased microRNAs in the second trimester in the control contributed to cell proliferation and neuron differentiation and that the rise in miR-137 in the third trimester led to neuron maturation. In the diabetic, higher levels of the microRNAs in the first trimester suggested alterations in cell proliferation and neuron differentiation. In conclusion, we showed that fetal-related microRNAs can be detected in the serum of pregnant woman and exhibit temporary regulation during pregnancy and that microRNAs involved in cell proliferation and neuron differentiation are upregulated under GDM. (c) 2017 The Authors. Published by Elsevier Ireland Ltd.

The purpose of this review was to search for experimental or clinical evidence on the effect of hyperglycemia in fetal programming to neurological diseases, excluding evident neural tube defects. The lack of timely diagnosis and the inadequate control of diabetes during pregnancy have been related with postnatal obesity, low intellectual and verbal coefficients, language and motor deficits, attention deficit with hyperactivity, problems in psychosocial development, and an increased predisposition to autism and schizophrenia. It has been proposed that several childhood or adulthood diseases have their origin during fetal development through a phenomenon called fetal programming. However, not all the relationships between the outcomes mentioned above and diabetes during gestation are clear, well-studied or have been related to fetal programming. To understand this relationship, it is imperative to understand how developmental processes take place in health, in order to understand how the functional cytoarchitecture of the central nervous system takes place; to identify changes prompted by hyperglycemia, and to correlate them with the above postnatal impaired functions. Although changes in the establishment of patterns during central nervous system fetal development are related to a wide variety of neurological pathologies, the mechanism by which several maternal conditions promote fetal alterations that contribute to impaired neural development with postnatal consequences are not clear. Animal models have been extremely useful in studying the effect of maternal pathologies on embryo and fetal development, since obtaining central nervous system tissue in humans with normal appearance during fetal development is an important limitation. This review explores the state of the art on this topic, to help establish the way forward in the study of fetal programming under hyperglycemia and its impact on neurological and psychiatric disorders.

J. Neurochem. (2012)122, 872–882. The function of histamine in the adult central nervous system has been extensively studied, but data on its actions upon the developing nervous system are still scarce. Herein, we review the available information regarding the possible role for histamine in brain development. Some relevant findings are the existence of a transient histaminergic neuronal system during brain development, which includes serotonergic neurons in the midbrain and the rhombencephalon that coexpress histamine; the high levels of histamine found in several areas of the embryo nervous system at the neurogenic stage; the presence of histaminergic fibers and the expression of histamine receptors in various areas of the developing brain; and the neurogenic and proliferative effects on neural stem cells following histamine H₁‐ and H₂‐receptor activation, respectively. Altogether, the reviewed information supports a significant role for histamine in brain development and the need for further research in this field.

Intracellular calcium plays a pivotal role in central nervous system (CNS) development by regulating various processes such as cell proliferation, migration, differentiation, and maturation. However, understanding the involvement of calcium (Ca²⁺) in these processes during CNS development is challenging due to the dynamic nature of this cation and the evolving cell populations during development. While Ca²⁺ transient patterns have been observed in specific cell processes and molecules responsible for Ca²⁺ homeostasis have been identified in excitable and non-excitable cells, further research into Ca²⁺ dynamics and the underlying mechanisms in neural stem cells (NSCs) is required. This review focuses on molecules involved in Ca²⁺ entrance expressed in NSCs in vivo and in vitro, which are crucial for Ca²⁺ dynamics and signaling. It also discusses how these molecules might play a key role in balancing cell proliferation for self-renewal or promoting differentiation. These processes are finely regulated in a time-dependent manner throughout brain development, influenced by extrinsic and intrinsic factors that directly or indirectly modulate Ca²⁺ dynamics. Furthermore, this review addresses the potential implications of understanding Ca²⁺ dynamics in NSCs for treating neurological disorders. Despite significant progress in this field, unraveling the elements contributing to Ca²⁺ intracellular dynamics in cell proliferation remains a challenging puzzle that requires further investigation.

Background: During rat development, histamine (HA) is one of the first neuroactive molecules to appear in the brain, reaching its maximal value at embryonic day 14, a period when neurogenesis of deep layers is occurring in the cerebral cortex, suggesting a role of this amine in neuronal specification. We previously reported, using high-density cerebrocortical neural precursor cultures, that micromolar HA enhanced the effect of fibroblast growth factor (FGF)-2 on proliferation, and that HA increased neuronal differentiation, due to HA type 1 receptor (H₁R) activation. Results: Clonal experiments performed here showed that HA decreased colony size and caused a significant increase in the percentage of clones containing mature neurons through H₁R stimulation. In proliferating precursors, we studied whether HA activates G protein-coupled receptors linked to intracellular calcium increases. Neural cells presented an increase in cytoplasmic calcium even in the absence of extracellular calcium, a response mediated by H₁R. Since FGF receptors (FGFRs) are known to be key players in cell proliferation and differentiation, we determined whether HA modifies the expression of FGFRs1-4 by using RT-PCR. An important transcriptional increase in FGFR1 was elicited after H₁R activation. We also tested whether HA promotes differentiation specifically to neurons with molecular markers of different cortical layers by immunocytochemistry. HA caused significant increases in cells expressing the deep layer neuronal marker FOXP2; this induction of FOXP2-positive neurons elicited by HA was blocked by the H₁R antagonist chlorpheniramine in vitro. Finally, we found a notable decrease in FOXP2+ cortical neurons in vivo, when chlorpheniramine was infused in the cerebral ventricles through intrauterine injection. Conclusion: These results show that HA, by activating H₁R, has a neurogenic effect in clonal conditions and suggest that intracellular calcium elevation and transcriptional up-regulation of FGFR1 participate in HA-induced neuronal differentiation to FOXP2 cells in vitro; furthermore, H₁R blockade in vivo resulted in decreased cortical FOXP2+ neurons.

Increased neuron telencephalic differentiation during deep cortical layer formation has been reported in embryos from diabetic mice. Transitory histaminergic neurons within the mesencephalon/rhombencephalon are responsible for fetal histamine synthesis during development, fibers from this system arrives to the frontal and parietal cortex at embryo day (E) 15. Histamine is a neurogenic factor for cortical neural stem cells in vitro through H1 receptor (H1R) which is highly expressed during corticogenesis in rats and mice. Furthermore, in utero administration of an H1R antagonist, chlorpheniramine, decreases the neuron markers microtubuline associated protein 2 (MAP2) and forkhead box protein 2. Interestingly, in the diabetic mouse model of diabetes induced with streptozotocin, an increase in fetal neurogenesis in terms of MAP2 expression in the telencephalon is reported at E11.5. Because of the reported effects on cortical neuron differentiation of maternal diabetes in one hand and of histamine in the other, here the participation of histamine and H1R on the increased dorsal telencephalic neurogenesis was explored. First, the increased neurogenesis in the dorsal telencephalon at E14 in diabetic rats was corroborated by immunohistochemistry and Western blot. Then, changes during corticogenesis in the level of histamine was analyzed by ELISA and in H1R expression by qRT-PCR and Western blot and, finally, we tested H1R participation in the increased dorsal telencephalic neurogenesis by the systemic administration of chlorpheniramine. Our results showed a significant increase of histamine at E14 and in the expression of the receptor at E12. The administration of chlorpheniramine to diabetic rats at E12 prevented the increased expression of BetaIII-tubulin and MAP2 mRNAs (neuron markers) and partially reverted the increased level of MAP2 protein at E14, concluding that H1R have an important role in the increased neurogenesis within the dorsal telencephalon of embryos from diabetic rats. This study opens new perspective on the participation of HA and H1R receptor in early corticogenesis in health and disease.