Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors

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.

Histamine H1 Receptors in Neural Stem Cells Are Required for the Promotion of Neurogenesis Conferred by H3 Receptor Antagonism following Traumatic Brain Injury

“…These findings suggest that the H1R in NSCs is required for the promotion of its differentiation provided by H3R antagonism. Since NSCs also express H3R (Escobedo-Avila et al., 2014, Molina-Hernandez and Velasco, 2008), we examined a direct effect of H3R- or H1R-related drugs and knockdown of H3R on NSC differentiation in vitro to further confirm that H1R, but not H3R, in NSCs is involved in the promotion of neurogenesis conferred by H3 antagonists. We found that both histamine and the H1 agonist histamine trifluoromethyl toluidide (HTMT), but not thioperamide, promoted NSC differentiation (Figures S4A, S4B, S4D, and S4E).…”

Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome

“…In addition, data on the subventricular zone cell culture from early postnatal mice have shown that histamine promotes neural differentiation to GABAergic neurons via HRH1 (Bernardino et al, ). Recently, histamine was shown to impair development of midbrain dopamine neurons via HRH1 (Escobedo‐Avila et al, ).…”

Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation

“…The neurotoxic effect induced by histamine was prevented by blocking H1R. Recently, it was also shown that histamine impairs midbrain DA development in vivo via H1R activation [ 66 ]. However, so far, the cellular and molecular mechanisms behind histamine-induced DA toxicity in the adult brain in vivo are not known.…”