Histamine and the striatum

Abstract

The neuromodulator histamine is released throughout the brain during periods of wakefulness. Combined with an abundant expression of histamine receptors, this suggests potential widespread histaminergic control of neural circuit activity. However, the effect of histamine on many of these circuits is unknown. In this review we will discuss recent evidence for histaminergic modulation of the basal ganglia circuitry, and specifically its main input nucleus; the striatum. Furthermore, we will discuss recent findings of histaminergic dysfunction in several basal ganglia disorders, including in Parkinson's disease and most prominently, in Tourette's syndrome, which has led to a resurgence of interest in this neuromodulator. Combined, these recent observations not only suggest a central role for histamine in modulating basal ganglia activity and behaviour, but also as a possible target in treating basal ganglia disorders.This article is part of the Special Issue entitled ‘Histamine Receptors’.

Histaminergic modulation in Tourette syndrome

“…Patients with the W317X mutation of HDC are unable to synthesize histamine and depend on the activity of HDC encoded by the non-mutated second allele. The presence of specific psychiatric comorbidities in some male members of this pedigree could also be explained by a dysfunction in the histaminergic system, as overriding inhibition of competing pathways within parallel cortico-striato-thalamo-cortical loops can hinder behavioral switching as seen in obsessivecompulsive disorder [89]. A more general association of histaminergic pathways with TS was identified by analysis of rare CNVs in a subsequent study [77].…”

“…Interestingly, we have recently seen increasing consensus that TS is a heterogeneous condition from both the phenotypic and genotypic points of view. Studies conducted using principal-component factor analysis [90][91][92][93][94][95], hierarchical cluster analysis [90,93,94,96] and latent class analysis [97,98] [99], a key region for the pathophysiology of TS, as altered striatal histaminergic-dopaminergic tone has been shown to potentially result in tic generation [89].…”

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

“…We also examined the Akt target GSK3␤-Ser 9 and found that it, too, was modulated by RAMH treatment (Fig. 4B).…”

“…Histamine (HA) is produced in the tuberomamillary nucleus of the posterior hypothalamus; these neurons project broadly throughout the brain, including to the striatum (7). HA receptors are prominent throughout the basal ganglia (7,8), but their function in modulating this circuitry is not well understood, and very few studies have examined their functional importance in vivo (9).…”

“…Recent clinical data have focused new attention on modulation of the basal ganglia by HA (9). A dominant-acting loss-of-function mutation in the HA biosynthetic enzyme histidine decarboxylase (Hdc) has been implicated as a rare cause of Tourette syndrome (16); other genetic analyses have suggested abnormalities in histaminergic signaling in Tourette syndrome more broadly (17,18).…”