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Review
. 2021 Jul 14:15:680214.
doi: 10.3389/fnins.2021.680214. eCollection 2021.

Histamine, Neuroinflammation and Neurodevelopment: A Review

Elliott Carthy  1 , Tommas Ellender  1   2
Affiliations
Review

Histamine, Neuroinflammation and Neurodevelopment: A Review

Elliott Carthy et al. Front Neurosci. .

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.

Keywords: astrocytes; brain; histamine; mast cells; microglia; neurodevelopment; neurodevelopmental disorders; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The interactions between mast cells, astrocytes and microglia can impact levels of histamine and neuroinflammation influencing neurodevelopment.
FIGURE 2
FIGURE 2
Interactions and mediators between mast cells, microglia and astrocytes in the brain. Bidirectional interactions are demonstrated between each cell type with the mediators involved in boxes. Different mediators are released in response to cellular activation, which are shown for each cell type. Image created with BioRender.com. ATP, adenosine triphosphate; BDNF, brain derived neurotrophic factor; CCL5, C–C motif chemokine ligand 5; C5a, complement 5a; CXCR4, CXC chemokine receptor 4; GDNF, glial derived neurotrophic factor; IL, interleukin; MCP, mast cell protease; NO, nitric oxide; NT3, neurotensin 3; ROS, reactive oxygen species; TLR, toll like receptor; TNF-α, tumor necrosis factor alpha.
FIGURE 3
FIGURE 3
Released modulators from mast cells, microglia and astrocytes can impact on developing neurons in the brain. Image created with BioRender.com. BDNF, brain derived neurotrophic factor; CX3CL, CX3C chemokine ligand 1; CX3CL, CX3C chemokine receptor; GDNF, glial derived neurotrophic factor; IGF-1, insulin-like growth factor 1; IL, interleukin; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotensin 3; TLR, toll like receptor; TNF-α, tumor necrosis factor alpha.
See this image and copyright information in PMC

References

    1. Abelson J. F., Kwan K. Y., O’roak B. J., Baek D. Y., Stillman A. A., Morgan T. M., et al. (2005). Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310 317–320. 10.1126/science.1116502 - DOI - PubMed
    1. Ahmad S. F., Nadeem A., Ansari M. A., Bakheet S. A., Al-Mazroua H. A., Khan M. R., et al. (2019). The histamine-4 receptor antagonist JNJ7777120 prevents immune abnormalities by inhibiting RORgammat/T-bet transcription factor signaling pathways in BTBR T(+) Itpr3(tf)/J mice exposed to gamma rays. Mol. Immunol. 114 561–570. 10.1016/j.molimm.2019.09.007 - DOI - PubMed
    1. Albin R. L., Mink J. W. (2006). Recent advances in Tourette syndrome research. Trends Neurosci. 29 175–182. 10.1016/j.tins.2006.01.001 - DOI - PubMed
    1. Ales K., Wraber B., Lipnik-Stangelj M. (2008). The synergistic effect of histamine and IL-6 on NGF secretion from cultured astrocytes is evoked by histamine stimulation of IL-6 secretion via H1-receptor-PKC-MAPK signalling pathway. Inflamm. Res. 57 S33–S34. - PubMed
    1. Alexander J., Potamianou H., Xing J., Deng L., Karagiannidis I., Tsetsos F., et al. (2016). Targeted Re-Sequencing approach of candidate genes implicates rare potentially functional variants in tourette syndrome etiology. Front. Neurosci. 10:428. 10.3389/fnins.2016.00428 - DOI - PMC - PubMed

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