The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry

https://doi.org/10.1016/j.pnpbp.2016.10.002Get rights and content

Highlights

  • Brain region specific signaling of H3R

  • Activation of H3R in the striatum is Gi independent.

  • Striatal H3R triggers MAPK activation in D1-MSNs and AKT/GSK3β in D2-MSNs.

  • Aberrant histaminergic function is a potential cause of tic disorders.

  • H3R as a target for treating neuropsychiatric disorders and addictions

Abstract

Histaminergic dysfunction has been recently linked to tic disorders and to aberrant striatal function. There is a particular interest in the histamine 3 receptor (H3R) due to its clinical implications for treating multiple disorders and its high expression in the brain. Striatal histamine (HA) modulates through the H3R in complex ways the release of striatal neurotransmitters into this brain region. The H3R has been classically described to be coupled to Gi, although there is evidence that revealed that striatal H3R forms heteromers with the dopamine receptors 1 and 2 in the medium spiny neurons (MSNs) than changes this signaling. Moreover, new data described for the first time a complete, segregated and time dependent signaling after H3R activation in the two types of MSNs (D1R-MSNs and D2R-MSNs). The aim of this review is to update the role of HA and H3R in striatal function at a molecular and signaling levels.

Introduction

The origin of the histaminergic circuit in the brain it is located in the tuberomammillary nucleus (TMN) of the hypothalamus, a brain structure classically related to thermoregulation, sleep and regulation of satiety (Provensi et al., 2014, Sethi et al., 2012, Yu et al., 2014). Histamine (HA) is synthetized by l-histidine decarboxylase (HDC), the expression of this enzyme is restricted to a cluster of cells that widely project to multiple brain regions (Panula and Nuutinen, 2013). In the brain, neurons can express either H1R, H2R and H3R (with multiple splice variants) whereas the H4R localization is restricted to the resident microglia (Ferreira et al., 2012, Zhu et al., 2014). The HA receptors differs not only in its homology and localization but also in their downstream signaling and complexity of its signaling.

H1R is a Gq/11 coupled receptor, which in result triggers release of intracellular Ca2 + through phospholipase C (PLC) and protein kinase C activation (PKC) (Haas and Panula, 2003). H2R elevates cAMP levels through a Gs dependent mechanism which in turn produce activation protein kinase A (PKA), this lead to a profound change in neuronal output (Haas et al., 2008). On the other hand, H4R is coupled to Gi but with scarce information about its role, although there is new promising research that is elucidating its functionality in health and disease (Dong et al., 2014, Ferreira et al., 2012, Frick et al., 2016). Classically, H3R has been described as a receptor that exerts its effects through a Gi mechanism (Leurs et al., 2005), notwithstanding there is a growing body of evidence that points out different signaling pathways that depends on cell type and brain region (Sadek et al., 2016). Being this receptor of preponderant importance among the HA receptors in the brain because of its translational potential as target for multiple psychiatric disorders (Ellenbroek and Ghiabi, 2014).

The heterogeneity of the areas innervated across the brain by histaminergic cells shows the panoply of effects that this neurotransmitter can generate on different behaviors (Furini et al., 2014). The expression of HDC has been evaluated in multiple target areas, these data showed that the striatum has six or seven times the amount of HDC compared to the cortex, cerebellum or hippocampus (Krusong et al., 2011). This fact does not disregard the importance of histamine for proper functioning of the areas mentioned above, although reveals a preponderant histaminergic innervation of the striatum over other regions. The striatum controls motor outputs, habit formation and the expression of tics in pathological disorders (Bronfeld and Bar-Gad, 2013, Graybiel and Grafton, 2015). Recent advances that linked histaminergic circuit impairment and striatal dysfunction to tic disorders propose a critical role of this neurotransmitter in this structure.

The aim of this review will be to update the current knowledge regarding the function of striatal histamine in health and disease with a particular focus on: H3 receptor signaling, interaction with other neurotransmitter and behavioral effects.

Section snippets

Basic striatal architecture

The striatum receives multiple inputs from cortical areas, hypothalamus, thalamus, and other structures. The large majority of striatal neurons are GABAergic medium spiny neurons (MSNs), of which there are two types. MSNs of the “direct” (striatonigral) pathway express the D1R dopamine (DA) receptor; MSNs of the “indirect” (striatopallidal) pathway express the D2R (Gerfen and Surmeier, 2011). Striatonigral MSNs projects to the entopeduncular nucleus (which is analogous to the internal segment

Modulation of striatal afferents by H3 receptor

One of the main effects of HA into striatal circuitry is how it modulates release of neurotransmitters into this structure. Glutamate release from cortical afferents is inhibited through the H3R receptor (Molina-Hernandez et al., 2001), also it has been shown that H3 stimulation of these cortical afferents produce a depression in synaptic transmission and field potentials (Doreulee et al., 2001). In this sense, elegant experiment using optogenetics have shown that HA through the H3 receptor it

Classical and non-classical H3 receptor signaling

The H3R is generally coupled to Gαi as was mentioned above, activation of this receptor inhibits the adenylyl cyclase which in turn reduces cAMP production. This mechanism it seems to be the one acting when the H3R is pre-synaptically located in striatal afferents (Haas et al., 2008) with some exceptions a was previously discussed above. There has been a general idea that H3R were only expressed in the MSNs as a presynaptic receptor, although it was not completely clear. Biophysical studies in

Histaminergic and H3 receptor functioning and its role in tic disorders

The nonsense mutation W317X in the HDC gene in a family with a two-generation pedigree in which Gilles de la Tourette's syndrome (TS) is segregated in an autosomal dominant fashion (Ercan-Sencicek et al., 2010). The histaminergic dysregulation in TS was further confirmed in an independent study performed in a large population of European patients with TS which showed mutations in the HDC gene (Karagiannidis et al., 2013). Mice who lacks this gene recapitulate core symptomatology of TS like

Conclusions and future directions

Multiple groups have substantially advanced into the knowledge of how HA modulates the CNS. The histaminergic circuit showed to be complex not only by its distribution, but also by the differential signaling that the H3R can trigger depending on the cell type and brain region (Fig. 1). Further studies in the histaminergic circuit it is necessary for a more extensive characterization of this enigmatic neurotransmitter in the brain. The evidence that points out a role of HA in neuropsychiatric

Acknowledgements

This work has been supported by Yale University and the State of Connecticut.

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