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    • The mechanistic basis of a PAE induced reduction in HDC

    2021-11-22

    The mechanistic basis of a PAE-induced reduction in HDC isoform expression is unclear at present. These reductions may be a consequence of reduced histaminergic innervation of PAE-affected brain regions. Given that these three brain regions are anatomically more distant from the ventral hypothalamus than, for example, the caudate nucleus, it is possible that the relatively longer paths for Sumatriptan to navigate to more distant brain regions during neurodevelopment were more susceptible to PAE. A more detailed examination of the development of the histaminergic innervation during the third week of gestation and early neonatal period could address this question. An alternative interpretation may be that PAE did not directly affect histaminergic axonal innervation to PAE-affected brain regions, but may have affected HDC levels in histamine nerve terminals of these regions, possibly by impairing anterograde transport or axonal trafficking of HDC to nerve terminals. The functional implications of reduced HDC expression in PAE-affected brain regions are not known at present. As HDC is the rate-limiting step in the conversion of histidine to transmitter-specific histamine, a reduction in HDC activity could imply a diminished capacity to produce transmitter-specific histamine. One approach to addressing this question would be to directly measure HDC activity in PAE-affected brain regions. Reduced HDC activity could imply diminished histaminergic modulation of local excitatory and inhibitory neural circuitry. A single early study by Rawat (1980) reported that prenatal ethanol exposure during 4 days of gestation using a 6% ethanol liquid diet did not affect HDC activity in fetal or neonatal brain. However, this report did not provide information on peak maternal ethanol levels nor details about brain regions analyzed. Thus, it would be difficult to compare these results with a study employing our moderate PAE paradigm. Another experimental approach that could be considered using a mouse model of moderate drinking during pregnancy would be to employ HDC-Cre mice with a floxed fluorescent transporter in combination with confocal microscopy to more directly quantify axonal densities in affected brain regions. The observation that moderate PAE alters H3 receptor-effector coupling in dentate gyrus, cerebellar, and cortical brain regions (Varaschin et al., 2018) raised questions about whether the number or function of other histamine receptor subtypes may be altered by PAE. To date, we have focused primarily on the histamine H2 receptor system. Histamine H2 receptor distribution was relatively high throughout the brain (Fig. 5A), generally 6-fold greater than the density of H3 receptor binding previously reported (Varaschin et al., 2018). However, in contrast to the results reported previously for H3 receptor density (Varaschin et al., 2018), moderate PAE did not affect the density of H2 receptor binding in any of the eight brains regions measured (Fig. 5B). In the case of H3 receptors, H3 receptor-effector coupling and H3 agonist-mediated inhibition of glutamate release were elevated in PAE rat offspring (Varaschin et al., 2018). Given this, we established an assay to measure H2 receptor-effector coupling using the selective H2 receptor agonist amthamine. Amthamine dose-dependently increased cAMP accumulation in dentate gyrus over roughly a 2-order magnitude increase in amthamine concentration, suggesting that the agonist was binding to a single non-interacting population of H2 receptors (Fig. 6A). Subsequently, we observed that PAE did not affect either basal cAMP accumulation or half-maximally and maximally effective concentrations of amthamine (Fig. 6B). These results suggest that neither the affinity (Kd) nor the maximal H2 receptor agonist-mediated response (Remax) were affected by PAE. Thus, it does not appear that moderate PAE has altered histamine H2 receptor function in a manner similar to its effects on histamine H3 receptor function. A similar lack of effect was reported previously for dopamine D2 receptor-stimulated cAMP accumulation in PAE offspring (Druse, Tajuddin, Eshed, & Gillespie, 1994). Future studies are planned to examine the impact of PAE on histamine H1 receptor density and H1 receptor-effector coupling. One limitation of these studies is that while different sexes were used in different experiment types, both sexes were not examined in any of the studies. While we have yet to note any sex-related differences in biochemical studies conducted in the past, future studies will be required to ascertain whether there are sex-related differences associated with histamine neuron number, HDC levels, or histamine H2 receptor density.