Histamine, Neuroinflammation and Neurodevelopment: A Review.

Elliott Carthy,Tommas Ellender

doi:10.3389/fnins.2021.680214

Elliott Carthy, Tommas Ellender

Open Access

https://doi.org/10.3389/fnins.2021.680214

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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.

Highlights

Histamine is a biogenic monoamine as well as an endogenous neurotransmitter with a diverse array of physiological functions, ranging from local inflammatory responses to regulating synaptic transmission in the brain
In this Review, we have highlighted the importance of the biogenic amine, histamine, in modulating the development of key neuronal circuits that are implicated in neurodevelopmental disorders, such as autism spectrum disorders (ASD) and Tourette’s syndrome (TS) amongst others, as well as regulating inflammatory processes in the brain
Most studies have focused on neuronal sources of histamine but what remains unclear is to what extent other sources of histamine, for example from mast cells, participate in these processes and allow for interactions between neuronal and non-neuronal cells

Summary

INTRODUCTION

Histamine is a biogenic monoamine as well as an endogenous neurotransmitter with a diverse array of physiological functions, ranging from local inflammatory responses to regulating synaptic transmission in the brain. The striatum is the major input nucleus of the basal ganglia which both during early postnatal periods (Han et al, 2020) and in adulthood expresses high numbers of H1, H2, and H3 receptors (Haas and Panula, 2003), suggesting that histamine can act as a modulator of many processes in the basal ganglia (Bolam and Ellender, 2016) In both the striatum, and more generally in the brain, the first postnatal weeks are characterized by rapid increases in the number and strength of excitatory synaptic connections (Tepper et al, 1998; Kozorovitskiy et al, 2012; Peixoto et al, 2016; Krajeski et al, 2019; Peixoto et al, 2019) and these connections exhibit plastic changes (i.e., synaptic plasticity) which is crucial for their development and refinement (Calabresi et al, 1992a; Kreitzer and Malenka, 2008).

Receptor Antagonists

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