Long-Term Functional and Cytoarchitectonic Effects of the Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine During Gestation in the Rat Offspring Primary Motor Cortex

• Published in: Frontiers in neuroscience Vol. 15; p. 740282
• Main Authors: Valle-Bautista, Rocío, Márquez-Valadez, Berenice, Herrera-López, Gabriel, Griego, Ernesto, Galván, Emilio J., Díaz, Néstor-Fabián, Arias-Montaño, José-Antonio, Molina-Hernández, Anayansi
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 24.01.2022; Frontiers Media S.A
• Subjects: Brain architecture; Cell activation; Cell differentiation; Cerebral cortex; cerebral cortex development; chlorpheniramine; Cognition; Cortex (motor); cortical function; Cyclin-dependent kinase inhibitor p21; cytoarchitecture; Dendritic branching; Depolarization; Embryos; Excitability; Foxp2 protein; GTP-binding protein; Hindbrain; Histamine; Histamine H1 receptors; Histidine; Histidine decarboxylase; hitamine H1 receptor; Immunofluorescence; Juveniles; Laboratory animals; Motor activity; Neonates; Neostriatum; Neural stem cells; Neurogenesis; Neurons; Neuroscience; Pain perception; pregnancy; Values; United States > US
• ISSN: 1662-453X; 1662-4548; 1662-453X
• DOI: 10.3389/fnins.2021.740282

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 H 1 receptor activation in vitro . The in utero or systemic administration of chlorpheniramine (H 1 receptor antagonist/inverse agonist) during deep-layer cortical neurogenesis decreases FOXP2 neurons in the developing cortex, and H 1 R- 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 H 1 R 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 [ 3 H]-glutamate release from striatal slices. Overall, these results suggest long-lasting effects of blocking H 1 Rs during early neurogenesis that may impact the pathways involved in voluntary motor activity and cognition.