The Histamine H1 Receptor Participates in the Increased Dorsal Telencephalic Neurogenesis in Embryos from Diabetic Rats

Abstract

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 βIII-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.

Impaired Cortical Cytoarchitecture and Reduced Excitability of Deep-Layer Neurons in the Offspring of Diabetic Rats

“…Increased neurogenesis is supported by higher SATB2, FOXP2, and TBR1 levels in M1, and by results previously reported for embryos of diabetic mice and rats (Fu et al, 2006;Solís et al, 2017). However, results obtained in this study for the neuronal markers SATB2 and TBR1 showed discrepancies in neonates of diabetic dams.…”

“…In humans, maternal diabetes has been related to postnatal neurological impairment and psychiatric disorders due to fetal programming promoted by an inadequate environment ( Ornoy et al, 1999 , 2001 ; Bolaños et al, 2015 ; Márquez-Valadez et al, 2018 ), although these relationships are still poorly understood. Increased neurogenesis and early neuron maturation have been reported during corticogenesis in murine embryos exposed to high glucose ( Fu et al, 2006 ; Solís et al, 2017 ). However, to our knowledge, the postnatal consequences on neocortical cytoarchitecture and function have not been reported.…”

“…However, it is not clear if these phenomena exist in embryos without neural tube defects. We previously reported increased neuron differentiation and early neuron maturation during the cortical neurogenic peak (E14) in embryos without neural tube defects from diabetic rats, events that were associated to increased expression of neurogenic factors and the appearance of the high molecular mass isoform of the Microtubule-associated protein 2, MAP2 (Solís et al, 2017). The effect of high glucose on cerebral cortex development has been addressed.…”

Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects

“…Our group reported that histamine increases cortical and mesencephalic NSC neurogenesis through H 1 -receptor (H 1 R) activation. Both this neurotransmitter and H 1 R showed a significant increase in the cortical neuroepithelial of embryos from diabetic pregnant rats ( 66 – 68 ). In mammals, histamine is a neurotransmitter/neuromodulator in the adult brain, acting through G-protein coupled receptors [H 1 R, H 2 RH 3 R, and H 4 R] ( 69 , 70 ).…”

“…In the diabetic model, the cortical neuroepithelium of embryos without NTD showed increased neurogenesis (E14) as well as histamine concentration (E14) and H 1 R expression (E12). Interestingly, the systemic administration at E12 of chlorpheniramine (H 1 R antagonist/inverse agonist) partially prevented increased dorsal telencephalic neurogenesis in embryos from diabetic rats, suggesting the participation of this receptor in the impaired neurogenesis observed in embryos from the diabetic model ( 68 ). The relevance of the above findings is also supported by evidence on the effect of antihistamine drugs on controlling glycemia under diabetic conditions ( 77 ).…”