Histamine, Neuroinflammation and Neurodevelopment: A Review

Abstract

The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette’s syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.

Sexually Dimorphic Transcriptomic Changes of Developing Fetal Brain Reveal Signaling Pathways and Marker Genes of Brain Cells in Domestic Pigs

“…We identified histamine H1 receptor mediated signaling pathway, metabotropic glutamate receptor group III pathway, heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway, heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway, EGF receptor signaling pathway and CCKR signaling map that were enriched among DEGs of the male fetal brain only ( Table 3 ). Histamine plays key regulatory roles in controlling specific cell types of brain that express histamine G protein-coupled receptors [ 80 ]. Moreover, histamines mediate pro- as well as anti-inflammatory responses to cytokines.…”

Role of Brain Modulators in Neurodevelopment: Focus on Autism Spectrum Disorder and Associated Comorbidities

“…The histaminergic neurons were reported to originate early at E 13 in rodents, equivalent to second trimester in humans [ 141 ]. Early contribution of histamine to neurogenesis was described to be maintained by histamine supply from other neurons (i.e., noradrenergic) and mast cells [ 142 ]. In addition to neurogenesis, histamine was found to meditate synaptogenesis, synaptic maturation, synaptic plasticity, and neural circuit formation [ 142 ].…”

Food Intolerance: The Role of Histamine

“…Histamine is not only a neuromodulator, but also an actor in neuroinflammation and interactions between mast cells, microglia, and astrocytes. Histamine is a promising therapeutic target with potential roles in the prevention or treatment of signs and symptoms of various nervous system developmental disorders (NDDs) [63]; however, there are still no convincing studies substantiating the involvement of mast-cell-secreted histamine in modulating both neuroinflammation and synaptic development and plasticity in vivo. Studying the mechanisms of early modulation of mast cell function is of great importance, since it may provide a new therapeutic target for NDD, including Tourette's syndrome, autism spectrum disorders, attention deficit hyperactivity disorder, and schizophrenia [63].…”