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

Rocío Valle-Bautista; Berenice Márquez-Valadez; Gabriel Herrera-López; Ernesto Griego; Emilio J Galván; Néstor-Fabián Díaz; José-Antonio Arias-Montaño; Anayansi Molina-Hernández

doi:10.3389/fnins.2021.740282

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

Front Neurosci. 2022 Jan 24:15:740282. doi: 10.3389/fnins.2021.740282. eCollection 2021.

Authors

Rocío Valle-Bautista^{1

2}, Berenice Márquez-Valadez², Gabriel Herrera-López³, Ernesto Griego³, Emilio J Galván³, Néstor-Fabián Díaz², José-Antonio Arias-Montaño¹, Anayansi Molina-Hernández²

Affiliations

¹ Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico.
² Laboratorio de Investigación en Células Troncales y Biología del Desarrollo, Departamento de Fisiología y Desarrollo Celular, Subdirección de Investigación Biomédica, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Ciudad de México, Mexico.
³ Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico.

Abstract

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.

Keywords: cerebral cortex development; chlorpheniramine; cortical function; cytoarchitecture; hitamine H1 receptor; pregnancy.