Long-Term Functional and Cytoarchitectonic Effects of the Systemic Administration of the Histamine H₁ Receptor...

The transient histaminergic system is among the first neurotransmitter systems to appear during brain development in the rat mesencephalon/rhombencephalon. Histamine increases FOXP2-positive deep-layer neuron differentiation of cortical neural stem cells through H₁ receptor activation in vitro. The in utero or systemic administration of chlorpheniramine (H₁ receptor antagonist/inverse agonist) during deep-layer cortical neurogenesis decreases FOXP2 neurons in the developing cortex, and H₁R- or histidine decarboxylase-knockout mice show impairment in learning and memory, wakefulness and nociception, functions modulated by the cerebral cortex. Due to the role of H₁R in cortical neural stem cell neurogenesis, the purpose of this study was to evaluate the postnatal impact of the systemic administration of chlorpheniramine during deep-layer cortical neuron differentiation (E12-14) in the primary motor cortex (M1) of neonates (P0) and 21-day-old pups (P21). Chlorpheniramine or vehicle were systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats at gestational days 12-14, and the expression and distribution of deep- (FOXP2 and TBR1) and superficial-layer (SATB2) neuronal cortical markers were analyzed in neonates from both groups. The qRT-PCR analysis revealed a reduction in the expression of Satb2 and FoxP2. However, Western blot and immunofluorescence showed increased protein levels in the chlorpheniramine-treated group. In P21 pups, the three markers showed impaired distribution and increased immunofluorescence in the experimental group. The Sholl analysis evidenced altered dendritic arborization of deep-layer neurons, with lower excitability in response to histamine, as evaluated by whole-cell patch-clamp recording, as well as diminished depolarization-evoked [³H]-glutamate release from striatal slices. Overall, these results suggest long-lasting effects of blocking H₁Rs during early neurogenesis that may impact the pathways involved in voluntary motor activity and cognition.