Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology

Abstract

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 MAPK and Akt signaling in D1R dopamine receptor-expressing striatonigral medium spiny neurons (dMSNs) and D2R dopamine receptor-expressing striatopallidal MSNs (iMSNs). Here 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.

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

“…Intracellular dopamine‐dependent signaling was found to be altered in striatum of Hdc KO mice . Although we did not find difference in pCreb/Creb ratio between mutant and control mice, it might be still possible that alteration is evident only if D1‐ and D2‐MSN could be studied separately .…”

“…26 Intracellular dopamine-dependent signaling was found to be altered in striatum of Hdc KO mice. 5,51 Although we did not find difference in pCreb/Creb ratio between mutant and control mice, it might be still possible that alteration is evident only if D1-and D2-MSN could be studied separately. 8 On the other hand, striatal expression of dopamine receptors 1 and 2 and dopamine signaling proteins DARPP-32 and Step61 are similar in Hdc KO and WT mice.…”

Protective effect of Asarum sieboldii essential oil on ovalbumin induced allergic rhinitis in rat

“…Histamine is released by the contact of mast cells and basophils with allergens, and is the most important mediator in the nasal allergy. Histamine activates the H1 receptor on vascular endothelial cells of respiratory smooth muscle cells, which induces the increase in C-GMP in the cells, thus producing pro-inflammatory effects, resulting in small vessel dilatation, microvascular permeability, and increased gland secretion [25,26]. These are the important material basis of nasal mucosal edema, increased nasal respiratory resistance, and increased secretion in patients with AR.…”

The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H3 receptor

“…Previous work established dysregulation of both MAPK and Akt signalling pathways in the dorsal striatum of Hdc KO mice, both at baseline and after amphetamine challenge (Rapanelli et al, 2014). More recently, we have examined differential dysregulation of these signalling pathways in D 1 ‐ and D 2 receptor‐expressing MSNs (Rapanelli et al, 2018). Strikingly, we find abnormalities at baseline in the KO mice that are nearly identical to what is seen in wild type animals after systemic administration of a H 3 receptor agonist.…”

“…In D 1 receptor‐expressing dMSNs, activation of the MAPK signalling pathway is elevated. In D 2 receptor‐expressing iMSNs, MAPK activity is normal, but phosphorylation of Akt is reduced (Rapanelli et al, 2018). This parallelism—that signalling at baseline in the KOs so closely reproduces what is seen after H 3 receptor agonist treatment in wild types—is consistent with the proposal that constitutive effects of up‐regulated H 3 receptors in the striatum of Hdc KO mice explain much of the striatal dysregulation seen in these animals.…”