Striatal Subregion-selective Dysregulated Dopamine Receptor-mediated Intracellular Signaling in a Model of DOPA-responsive Dystonia. (1st May 2023)

• Record Type: Journal Article
• Authors: Roman, Kaitlyn M.; Briscione, Maria A.; Donsante, Yuping; Ingram, Jordan; Fan, Xueliang; Bernhard, Douglas; Campbell, Simone A.; Downs, Anthony M.; Gutman, David; Sardar, Tejas A.; Bonno, Sofia Q.; Sutcliffe, Diane J.; Jinnah, H.A.; Hess, Ellen J.
• Is Part Of: Neuroscience. Volume 517(2023)
• Page Start: 37
• Page End: 49
• Publication Date: 2023-05-01
• Subjects: protein kinase A -- extracellular signal-related kinase -- dystonia -- dopamine -- striatum; 6OHDA 6-hydroxydopamine -- D1Rs D1 dopamine receptors -- D2Rs D2 dopamine receptors -- DRD DOPA-responsive dystonia -- dSPNs direct pathway SPNs -- ERK extracellular signal-related kinase -- iSPNs indirect pathway SPNs -- PKA protein kinase A -- p-PKA-sub phospho-PKA substrate antibody -- SPNs spiny projection neurons; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2023.02.020
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Dopamine-mediated intracellular signal is dysregulated in dystonia. Abnormal intracellular signaling was differentially regulated in striatal subregions. ERK phosphorylation occurred in dorsomedial striatum but not dorsolateral striatum. Dopamine-mediated intracellular signal in dystonia was distinct from Parkinsonism. Abstract: Although the mechanisms underlying dystonia are largely unknown, dystonia is often associated with abnormal dopamine neurotransmission. DOPA-responsive dystonia (DRD) is a prototype disorder for understanding dopamine dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of dopamine and alleviated by the indirect-acting dopamine agonist l -DOPA. Although adaptations in striatal dopamine receptor-mediated intracellular signaling have been studied extensively in models of Parkinson's disease, another movement disorders associated with dopamine deficiency, little is known about dopaminergic adaptations in dystonia. To identify the dopamine receptor-mediated intracellular signaling associated with dystonia, we used immunohistochemistry to quantify striatal protein kinase A activity and extracellular signal-related kinase (ERK) phosphorylation after dopaminergic challenges in a knockin mouse model of DRD. l -DOPA treatment induced the phosphorylation of both protein kinase A substrates and ERK largely in D1 dopamine receptor-expressing striatal neurons. As expected, this response was blocked by pretreatment with the D1 dopamine receptor antagonist SCH23390. The D2 dopamine receptor antagonist raclopride also significantly reduced the phosphorylation of ERK; this contrasts with models of parkinsonism in which l -DOPA-induced ERK phosphorylation is not mediated by D2 dopamine receptors. Further, the dysregulated signaling was dependent on striatal subdomains whereby ERK phosphorylation was largely confined to dorsomedial (associative) striatum while the dorsolateral (sensorimotor) striatum was unresponsive. This complex interaction between striatal functional domains and dysregulated dopamine-receptor mediated responses has not been observed in other models of dopamine deficiency, such as parkinsonism, suggesting that regional variation in dopamine-mediated neurotransmission may be a hallmark of dystonia.