Tourette’s Syndrome: Histamine

Author: Will Bowman

Molecular Structure of Histamine

In the past 4-5 years, Tourette’s Syndrome has been linked to an overall deficiency in histamine production in the brain. Histamine is synthesized from histidine within cells via histidine decarboxylase. Histamine is known to modulate behavior and physiological functions by interacting with histamine receptors which interact with neurotransmitter release (Pittenger, C, 2017).

A mutation in histamine decarboxylase (HDC), which is the rate-limiting step in histamine biosynthesis, is implicated as a genetic cause in rare cases. In a genetic study three single nucleotide polymorphisms in HDC in 241 Chinese families were identified, not linked to rare mutation. Histamine signalling pathway is mediated by four G-protein coupled receptors (H1-H4) within the striatum and cortex of the brain. The H3 receptor is linked to regulation of dopamine and serotonin, which are also associated with Tourette’s syndrome (Dong, H. et al. 2016). Histamine receptors H2 and H4 have been shown to be down-regulated upon decreased histamine production, while H1 receptors are unchanged and H3 receptors are upregulated. H3 receptors therefore are interesting in striatum as increased expression may influence activity without the presence of histamine. The addition of H3 agonists, such as RAMH and immepip, produced Tourette’s Syndrome stereotypies in knockout mice, implying an effect despite lowered levels of histamine in the organism. H3 is classically considered a presynaptic receptor involved in negative regulation of transmitter release, both of histamine and other neurotransmitters. However, H3 is also present post-synaptically and interacts with Dopamine 1 and 2 receptors (D1R, D2R). H3 is reported to inhibit dopamine release, however more recent data show that H1 is a more likely candidate to modulate dopamine levels. It was shown in knockout mice studies that H3 agonists immepip and RAMH do not affect intrastriatal dopamine levels in wild-type mice, while H1 antagonists are able to increase intrastriatal dopamine levels. It is known that there is increased dopamine turnover in striatum and increased dopamine extra-synaptic levels in hdc knockout mice, suggesting altered dopamine signalling (Pittenger, C, 2017).

Currently HDC knockout mice are the main vehicle for research on histamine signalling in relation to Tourette’s Syndrome, but recently zebrafish have been demonstrated as a useful tool to study the histaminergic systems. Early exposure to valpronic acid is linked to disrupted histaminergic, dopaminergic and noradrenergic systems. In this way, zebrafish were impaired in observable sociability stereotypies that can be related to neuropsychiatric disorders (Baronio, D. et al. 2018).

The connection between Tourette’s Syndrome and histamine dysregulation is still recent, and therefore is incomplete.The field still stands to answer the detailed mechanisms of histamine regulation on striatal dopamine. Hopefully, with the introduction of a new model organism, this work can be furthered and elucidate the connections newly established between histamine dysregulation, dopamine regulation, and the broader pathologies of Tourette’s Syndrome.





Baldan, Lissandra Castellan, Kyle A. Williams, Jean-Dominique Gallezot, Vladimir Pogorelov, Maximiliano Rapanelli, Michael Crowley, George M. Anderson, et al. 2014. “Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice.” Neuron 81 (1): 77–90.


Baronio, Diego, Henri A. J. Puttonen, Maria Sundvik, Svetlana Semenova, Essi Lehtonen, and Pertti Panula. 2018. “Embryonic Exposure to Valproic Acid Affects the Histaminergic System and the Social Behaviour of Adult Zebrafish (Danio Rerio).” British Journal of Pharmacology 175 (5): 797–809.


Dong, He, Wenmiao Liu, Meixin Liu, Longqiang Xu, Qiang Li, Ru Zhang, Xin Zhang, and Shiguo Liu. 2016. “Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study.” PloS One 11 (8): e0160265.


Pittenger, Christopher. 2017. “Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions.” Handbook of Experimental Pharmacology 241: 189–215.


Wright, C., J. H. Shin, A. Rajpurohit, A. Deep-Soboslay, L. Collado-Torres, N. J. Brandon, T. M. Hyde, et al. 2017. “Altered Expression of Histamine Signaling Genes in Autism Spectrum Disorder.” Translational Psychiatry 7 (5): e1126.


Xu, Meiyu, Lina Li, Hiroshi Ohtsu, and Christopher Pittenger. 2015. “Histidine Decarboxylase Knockout Mice, a Genetic Model of Tourette Syndrome, Show Repetitive Grooming after Induced Fear.” Neuroscience Letters 595 (May): 50–53.

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