Abstract
BackgroundHistamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. To study the effect of HA receptor stimulation on dopamine neuron generation, we administered HA to dopamine progenitors, both in vitro and in vivo.ResultsCultured embryonic day 12 (E12) VM neural stem/progenitor cells expressed transcripts for HA receptors H1R, H2R and H3R. These undifferentiated progenitors increased intracellular calcium upon HA addition. In HA-treated cultures, dopamine neurons significantly decreased after activation of H1R. We performed intrauterine injections in the developing VM to investigate HA effects in vivo. HA administration to E12 rat embryos notably reduced VM Tyrosine Hydroxylase (TH) staining 2 days later, without affecting GABA neurons in the midbrain, or serotonin neurons in the mid-hindbrain boundary. qRT-PCR and Western blot analyses confirmed that several markers important for the generation and maintenance of dopaminergic lineage such as TH, Lmx1a and Lmx1b were significantly diminished. To identify the cell type susceptible to HA action, we injected embryos of different developmental stages, and found that neural progenitors (E10 and E12) were responsive, whereas differentiated dopaminergic neurons (E14 and E16) were not susceptible to HA actions. Proliferation was significantly diminished, whereas neuronal death was not increased in the VM after HA administration. We injected H1R or H2R antagonists to identify the receptor responsible for the detrimental effect of HA on dopaminergic lineage and found that activation of H1R was required.ConclusionThese results reveal a novel action of HA affecting dopaminergic lineage during VM development.
Highlights
Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals
After removing Fibroblast growth factor (FGF)-2 from cultures, cells readily differentiate into neurons (MAP2- and β-III Tubulin-positive), astrocytes (Glial Fibrillary Acidic Protein, glial fibrillary acidic protein (GFAP)-positive) and oligodendrocytes (O4-positive) (Figure 1B), confirming that our cultures are neural stem/progenitor cell (NSPC)
Previous work has demonstrated that mRNAs for histaminergic receptors are present in rodent embryos from E14 onwards [18,20,21], but no information has been reported regarding the expression of these receptors at earlier stages of embryogenesis neither in the ventral midbrain (VM) tissue, nor in midbrain NSPC in vitro
Summary
Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. Histamine (HA) is a neurotransmitter that participates in the sleep cycle, motor activity, synaptic plasticity and memory [1,2,3,4,5]. The adult mammalian brain contains somas of HA-producing neurons in the hypothalamic tuberomamillary nucleus, and its projections reach most of the CNS [3,4,6]. The transitory expression of HDC in the midbrain, together with elevated HA levels, and the expression of HRs, coincides with periods of dopaminergic specification [24], suggesting that HA might influence dopamine (DA) neuron generation in the ventral midbrain (VM). By E16, all DA cells are post-mitotic and their axons are en route to reach forebrain structures such as the striatum and the cerebral cortex [25,26]
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