The histaminergic neurotransmitter system : its development and role in neuronal plasticity in zebrafish, Danio rerio

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http://urn.fi/URN:ISBN:978-952-10-8137-8
Title: The histaminergic neurotransmitter system : its development and role in neuronal plasticity in zebrafish, Danio rerio
Author: Sundvik, Maria
Contributor: University of Helsinki, Faculty of Medicine, Institute of Biomedicine, Anatomi
Neuroscience Center, University of Helsinki
Publisher: Helsingin yliopisto
Date: 2012-08-24
URI: http://urn.fi/URN:ISBN:978-952-10-8137-8
http://hdl.handle.net/10138/35585
Thesis level: Doctoral dissertation (article-based)
Abstract: The histaminergic neurotransmitter system is a modulatory system which regulates many functions in the vertebrate brain. In the mammalian brain, histaminergic neurons fire during waking and are involved in maintaining sleep-wake homeostasis. Furthermore, histamine has been implicated in neurodegenerative disorders. Patients suffering from Alzheimer s disease, Parkinson s disease and narcolepsy have alterations in this system. Histamine is produced from the amino acid ι-histidine by histidine decarboxylase (HDC). The aims of this study were to characterize the histaminergic system in zebrafish, a nonmammalian vertebrate, and to identify novel mechanisms in which the histaminergic system is involved. We found that histamine receptor ligands altered the behavior in larval zebrafish in a dose-dependent manner. Cloning and sequence analysis of the histamine receptors indicated that the zebrafish histamine receptors were similar to the corresponding mammalian receptors. We also studied the neurotransmitter phenotype of histaminergic neurons by immunohistochemistry and confocal microscopy and found that these neurons resemble those of rats. Immunohistochemical comparison of the histaminergic system in male and female adult brain revealed no significant differences in location, distribution, or neuron number, and thereby no differences between the sexes were observed. We studied the functions of the histaminergic system in hdc knockdown animals (morpholino oligonucleotide approach), and found that the neurotransmitter was important for mediating rapid behavioral responses to environmental cues, and that these behavioral responses were driven via the histamine receptor hrh1. We studied the interaction of histamine with a wakefulness associated neuropeptide system, hypocretin/orexin (hcrt), which is implicated in narcolepsy. We reported a novel mechanism for histamine that regulates development of the hcrt neurons. Transient knockdown of hdc with morpholino oligonucleotides and pharmacological inactivation of hrh1 with pyrilamine reduced the number of hcrt mRNA-positive neurons in zebrafish larvae. This effect was rescued by overexpression of hdc mRNA. Since histaminergic neurons play important roles in the central nervous system, we were interested in identifying factors that regulates the development of the histaminergic neurons themselves. We found that in the Alzheimer s disease-associated gene, presenilin1 (psen1), mutant zebrafish, the histaminergic system was altered. During the developmental and larval stages, the histamine neuron number was significantly reduced in psen1 mutants, whereas at the young adult age there was a significant increase in histamine neuron number in psen1 mutants in comparison to wild-type fish. These results showed us that psen1 was essential for the development and normal functioning of the histaminergic neurotransmitter system. Histamine is metabolized by histamine N-methyltransferase (HNMT), followed by monoamine oxidase (MAO). We studied the effect that pharmacological inhibition of MAO has on the locomotor behavior of fish. We found that pharmacological inhibition of the MAO enzyme mainly affects the serotonin system in zebrafish, with characteristic behavioral consequences that could be rescued. Taken together, the results of this thesis provide evidence that the histaminergic neurotransmitter system in zebrafish is similar to that in mammals. These results show that the zebrafish is an excellent tool in studies to provide novel insights into neurotransmitter system functions in the vertebrate central nervous system on both the mechanistic and behavioral levels. We found that the histaminergic system is important for rapid behavioral responses, affects the development of the hcrt neurotransmitter system, and is itself regulated in a temporal manner by psen1.Det histaminerga neurotransmittersystemet är ett modulatoriskt system som reglerar många funktioner i hjärnan hos vertebrater. Genom interaktion med receptorer i olika hjärnområden är histamin involverat i flera komplexa funktioner, från hormonal kontroll till kognition. Neuronalt histamin är främst känt för sin roll i övergången från sömn till vakenhet, i och med att dessa neuroner är aktiva när individen vaknar. Trots att neuronalt histamin studerats under flera årtionden, är det fortfarande oklart vilka faktorer som styr de histaminerga neuronernas utveckling, samt hur systemet samverkar med andra neurotransmittersystem på molekylär nivå. Förändringar i det histaminerga neurotransmittersystemet har kopplats till neurodegenerativa sjukdomar såsom Alzheimers sjukdom, Parkinsons sjukdom och narkolepsi. Trots detta är det oklart huruvida det histaminerga systemet är involverat i etiologin av sjukdomarna. Målsättningarna med denna avhandling var att karakterisera det histaminerga systemet i sebrafisk, och att identifiera nya mekanismer som medieras via det histaminerga systemet. Vi fann stora likheter mellan sebrafiskens och mammaliers histaminerga neurotransmittersystem, vilket tyder på att nya rön kan extrapoleras från fisk till däggdjur. Histamin produceras från aminosyran ι-histidin genom en reaktion katalyserad av histidindekarboxylas. Kortvarig inhibering av produktionen av histamin i sebrafiskyngel, resulterade i en beteendeförändring. De individer som saknade histamin var oförmögna att reagera på samma sätt som kontrollfiskarna på en snabb förändring i omgivningen. Resultaten indikerar att histamin är viktigt vid reglering av finmotorik, vilket även detekterats i patienter som diagnostiserats med Gilles de la Tourette syndrom. Dessutom fann vi att histamin via histamin receptor 1 reglerar utvecklingen av hypocretin/orexin (hcrt) systemet, vilket i sin tur är det neurotransmittersystem som kopplats till narkolepsi. Eftersom histamin medverkar i flera neuronala processer, identifierade vi en faktor essentiell för utvecklingen av histaminerga neuroner. Vi fann att presenilin 1, en gen associerad med Alzheimers sjukdom, reglerar utvecklingen av histaminerga neuroner. Resultaten sammanställda i denna avhandling visar att sebrafisken lämpar sig väl i studier angående det histaminerga systemet. Resultaten visar att sebrafisken utgör en utmärkt modell för nya rön i vertebraters centrala nervsystem, både på en mekanistisk och beteende nivå. Vi fann att det histaminerga systemet är viktigt för snabba beteendeförändringar, påverkar utvecklingen av hcrt neuroner och är självt reglerat av presenilin 1. Dessa resultat ger en ny infallsvinkel i studier av neurodegenerativa sjukdomar, såsom narkolepsi och Alzheimers sjukdom.
Subject: medicin, neurobiologi
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