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.
Highlights
Histamine (HA) participates in rat central nervous system (CNS) development
H1R blockade by the systemic or intrauterine administration of chlorpheniramine at embryo day 12 (E12) leads to a reduction in FOXP2+ deep-layer neurons in the dorsal telencephalon at E14
We found a reduction in the relative expression of Satb2 and Foxp2 to 21 and 56% of control values, respectively, in the frontal cerebral cortex of neonates from chlorpheniramine-treated rats, while Tbr1 relative expression was not affected (Figure 1B)
Summary
Histamine (HA) participates in rat central nervous system (CNS) development. A transitory fetal histaminergic system co-localizes with serotonin neurons in the mesencephalon/rhombencephalon at embryo day 12 (E12; Auvinen and Panula, 1988). Through H1R activation, HA promotes neuron differentiation of cortical neural stem cells (NSCs) obtained from E14 embryo and adult tissue (Molina-Hernández and Velasco, 2008; Bernardino et al, 2012). FOXP2 (marker of deep-layer neurons) is involved in learning motor skills, and specific mutations are related to verbal dyspraxia in humans and impaired ultrasonic vocalization and singing performance in rodents and birds, respectively. These functional processes are regulated by the cortex, basal ganglia, thalamus, and cerebellum (Burkett et al, 2018; Co et al, 2020; den Hoed et al, 2021). FOXP2 participates in the transition from NSCs to intermediate precursors (IP) required for neuron differentiation (Tsui et al, 2013)
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