Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising model of this pathophysiology. How alterations in the histamine system lead to neuropsychiatric disease, however, remains unclear. The H3R histamine receptor is elevated in the striatum of Hdc KO mice, and H3R agonists, acting in the dorsal striatum, trigger tic-like movements in the model. In wild-type mice, H3R in the dorsal striatum differentially regulates mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling in D1R dopamine receptor-expressing striatonigral medium spiny neurons (dMSNs) and D2R dopamine receptor-expressing striatopallidal MSNs (iMSNs), respectively. We examined the effects of H3R agonist treatment on MSN signaling in the Hdc-KO model. In dMSNs, MAPK signaling was elevated at baseline in the Hdc-KO model, resembling what is seen after H3R activation in WT animals. Similarly, in iMSNs, Akt phosphorylation was reduced at baseline in the KO model, resembling what is seen after H3R activation in WT animals. H3R activation in Hdc-KO mice further enhanced the baseline effect on Akt phosphorylation in iMSNs but attenuated the abnormality in MAPK signaling in dMSNs. These observations support the hypothesis that constitutive activity of upregulated H3R receptors in the Hdc-KO model mediates the observed alterations in baseline MSN signaling; but further activation of H3R, which produces tic-like repetitive movements in the model, has more complex effects.
Keywords: Tourette syndrome; dopamine receptor; histamine H3 receptor; histidine decarboxylase; medium spiny neurons; signaling pathway.
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