Storage of neural histamine and histaminergic neurotransmission is VMAT2 dependent in the zebrafish

Abstract

Monoaminergic neurotransmission is greatly dependent on the function of the vesicular monoamine transporter VMAT2, which is responsible for loading monoamines into secretory vesicles. The role of VMAT2 in histaminergic neurotransmission is poorly understood. We studied the structure and function of the histaminergic system in larval zebrafish following inhibition of VMAT2 function by reserpine. We found that reserpine treatment greatly reduced histamine immunoreactivity in neurons and an almost total disappearance of histamine-containing nerve fibers in the dorsal telencephalon and habenula, the most densely innervated targets of the hypothalamic histamine neurons. The reserpine treated larvae had an impaired histamine-dependent dark-induced flash response seen during the first second after onset of darkness, implying that function of the histaminergic network is VMAT2 dependent. Levels of histamine and other monoamines were decreased in reserpine treated animals. This study provides conclusive evidence of the relevance of VMAT2 in histaminergic neurotransmission, further implying that the storage and release mechanism of neural histamine is comparable to that of other monoamines. Our results also reveal potential new insights about the roles of monoaminergic neurotransmitters in the regulation of locomotion increase during adaptation to darkness.The function of most monoamine neurotransmitters is dependent on the vesicular release made possible by the vesicular monoamine transporter 2 (VMAT2). Serotonin and dopamine are loaded into secretory vesicles by VMAT2, and inhibition of VMAT2 leads to rapid depletion of these neurotransmitters through metabolism by the enzyme monoamine oxidase (MAO)1 . Since noradrenaline is synthesized from dopamine inside secretory vesicles 2 , VMAT2 inhibition also lowers noradrenaline levels 1 . VMAT2 inhibition by the indole alkaloid reserpine was previously used as a treatment for psychotic conditions 3 . Depression has often been reported as a side-effect of reserpine treatment, which was a key factor in the development of the monoamine depletion theory of depressive disorders and the reserpine treated animal model for depression, although the monoamine hypothesis has recently been challenged [4][5][6] . Taken together, these findings underline the significance of monoamine dependent neurotransmission in brain physiology.The role of VMAT2 in histaminergic neurotransmission remains unclear. Like the other monoamines, histamine has been described as a substrate for VMAT2 7 . In gastric enterochromaffin-like (ECL) cells, histamine storage is controlled by reserpine 8 , and reserpine induces changes in vesicle morphology and subcellular distribution of histamine 9 . However, histamine is not known to be significantly metabolized by MAO, but is rather metabolized by histamine N-methyltransferase (HNMT) in the brain, followed by subsequent metabolism by MAO 10,11 . In an explant culture from fetal rat hypothalamus, most histamine-immunoreactive neurons display VMAT2-immunoreactivity, w...

Vesicular monoamine transporter 2 (SLC18A2) regulates monoamine turnover and brain development in zebrafish

“…18 While ablation-studies indicate this behaviour is not dependent on the Mauthner cells, which are known to modulate rapid escape reactions in the zebrafish, 18 previous pharmacological evidence suggest that disrupted monoaminergic signalling leads to a stronger dark-flash response. 32,33 In our genetic study, the vmat2 −/− larvae displayed a stronger dark-flash response than their vmat2 +/+ siblings, reinforcing the findings from pharmacological studies.…”

“…The present results are in agreement with the previous data on WT zebrafish treated with reserpine during an early developmental stage. 33 The HPLC data showed an 85% reduction in the amount of histamine in vmat2 −/− larvae when compared with vmat2 +/+ siblings. Concomitantly, the number of hdcpositive cells in the brains of vmat2 mutants was increased by 30%, perhaps reflecting a homeostatic mechanism to upregulate histamine signalling.…”

Bsx Is Essential for Differentiation of Multiple Neuromodulatory Cell Populations in the Secondary Prosencephalon

“…Since we used nr5a1a staining only to demonstrate that forebrain patterning is normal, we concluded potential hybridization to those other genes to be rather inconsequential for our statement. Our vmat2 probe also has some similarity to a vmat1 transcript (XM_021478484.1), which, however, is not expressed in the larval zebrafish brain (Puttonen et al, 2017). We also found the expression patterns generated by all in situ hybridization probe sequences cloned in this study to match the expression patterns of the same gene as has been published previously (for references see Supplementary Table S1).…”

Histamine, Neuroinflammation and Neurodevelopment: A Review

“…The number of histamine-immunoreactive neurons in these regions then steadily decreases until E18, after which the histaminergic neurons of the TMN of the hypothalamus become detectable at E20 which project widely throughout the brain and form a main neuronal histaminergic source that persist into adulthood (Auvinen and Panula, 1988;Haas et al, 2008;Molina-Hernández et al, 2012). Neuronal histamine is stored within both the cell somata as well as within vesicles in axonal varicosities as packaged by the vesicular monoamine transporter (VMAT2) and is released by activated neurons (Haas et al, 2008;Puttonen et al, 2017). In addition, ependymal cells lining the ventricles also likely synthesize histamine as they express the synthesizing enzyme Hdc (Karlstedt et al, 2001a).…”