Abstract
The dopaminergic and histaminergic systems are the first to appear during the development of the nervous system. Through the activation of H1 receptors (H1Rs), histamine increases neurogenesis of the cortical deep layers, while reducing the dopaminergic phenotype (cells immunoreactive to tyrosine hydroxylase, TH+) in embryo ventral mesencephalon. Although the function of histamine in neuronal differentiation has been studied, the role of H1Rs in neurogenesis has not been addressed. For this purpose, the H1R antagonist/inverse agonist chlorpheniramine was systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats (gestational days 12–14, E12–14), and control and experimental embryos (E14 and E16) and pups (21-day-old) were evaluated for changes in nigro-striatal development. Western blot and immunohistochemistry determinations showed a significant increase in the dopaminergic markers’ TH and PITX3 in embryos from chlorpheniramine-treated rats at E16. Unexpectedly, 21-day-old pups from the chlorpheniramine-treated group, showed a significant reduction in TH immunoreactivity in the substantia nigra pars compacta and dorsal striatum. Furthermore, striatal dopamine content, evoked [3H]-dopamine release and methamphetamine-stimulated motor activity were significantly lower compared to the control group. These results indicate that H1R blockade at E14–E16 favors the differentiation of dopaminergic neurons, but hampers their migration, leading to a decrease in dopaminergic innervation of the striatum in post-natal life.
Highlights
The commitment and maturation of dopaminergic neurons is a complex process coordinated by secreted molecules and the expression of transcription factors, which are finely coordinated in a time and spatial manner (Hegarty et al, 2013)
The specification of these processes begins at embryo day 10.5 (E10.5) in the rat ventral mesencephalon (vMes), and committed dopaminergic neurons can be identified by the expression of the transcription factors Limhomeodomain 1A and 1B (LMX1A and LMX1B), and Forkhead box A1/2 (FOXA1/2) (Smidt et al, 2000; Andersson et al, 2006; Guerrero-Flores et al, 2017)
Immunofluorescence analysis showed that at E12 histamine H1 receptor (H1R)+ cells were preferentially located in the ventricular zone (VZ), where neural stem cells (NSCs) are located (Figure 2D)
Summary
The commitment and maturation of dopaminergic neurons is a complex process coordinated by secreted molecules (mainly sonic hedgehog and fibroblast growth factor 8) and the expression of transcription factors, which are finely coordinated in a time and spatial manner (Hegarty et al, 2013). The specification of these processes begins at embryo day 10.5 (E10.5) in the rat vMes, and committed dopaminergic neurons can be identified by the expression of the transcription factors Limhomeodomain 1A and 1B (LMX1A and LMX1B), and Forkhead box A1/2 (FOXA1/2) (Smidt et al, 2000; Andersson et al, 2006; Guerrero-Flores et al, 2017). The complete maturation and survival of dopaminergic neurons occurs at postnatal day 21, P21 (Oo and Burke, 1997)
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