Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Abnormal dopamine (DA) neurotransmission is consistently observed across many different forms of dystonia, but the DA defects that give rise to dystonia are poorly understood. L-DOPA-responsive dystonia (DRD) is considered a prototype disorder for understanding how abnormal DA neurotransmission evokes dystonia. DRD is characterized by childhood onset dystonia with diurnal fluctuation whereby symptoms worsen throughout the course of the day. The distinguishing feature of DRD is the dramatic improvement in symptoms after restoration of DA signaling with L-DOPA or DA agonists. Indeed, DRD is caused by mutations in genes critical for DA synthesis, including tyrosine hydroxylase (TH). DRD-causing TH mutations are associated with some residual TH activity whereas mutations that abolish TH activity cause childhood parkinsonism suggesting that TH activity and [DA] are critical determinants in the development of dystonia. However, the nature of the DA signaling dysfunction that gives rise to dystonia is unknown. To address this gap in our knowledge, we generated a knockin mouse bearing the human DRD-causing Q381K mutation in TH (DRD mice). Like the human disorder, DRD mice display reduced TH activity, a reduction in [DA], dystonic movements that worsen throughout the course of the active period and improvement in the dystonia in response to L-DOPA. Thus, DRD mice exhibit the core neurochemical and symptomatic features of human DRD, thereby providing us with the unprecedented opportunity to dissect the mechanisms underlying DRD from gene to behavior. Our preliminary data demonstrate that the dystonia is mediated by [DA] that is <1% of normal. A similar reduction in presynaptic DA in adults would cause parkinsonism. Therefore, divergent postsynaptic responses likely account for the differences in the neurological consequences of reduced DA transmission between Parkinson's disease (PD) and dystonia. Indeed, our preliminary data demonstrate D1R supersensitivity, hyperexcitability of medium spiny neurons (MSNs), a reduction in MSN dendrite number and abnormal corticostriatal innervation. Therefore, we will test the hypothesis that early life DA deficiency in combination with (mal)adaptive postsynaptic responses gives rise to dystonia by using a multidisciplinary approach to examine the pre- and postsynaptic consequences of reduced DA transmission associated with dystonia.
The Specific Aims are: 1. To elucidate the relationship between monoamine metabolism and the severity of dystonia. 2. To determine the DA receptor subtype(s) and signaling defects that contribute to the dystonia. 3. To delineate alterations in th intrinsic and synaptic properties of D1 and D2R-expressing MSNs. 4. To examine the dendritic morphology and ultrastructural changes in corticostriatal synapses onto D1R and D2R-expressing MSNs in response to early-life DA deprivation in DRD mice.

Public Health Relevance

These experiments will help to elucidate the pathophysiological role of DA in dystonia and may therefore lead to novel therapeutic strategies for the treatment of dystonia. In addition to having direct relevance to the many forms of dystonia associated with abnormal DA neurotransmission, the proposed experiments may also provide insight into the pathogenesis of `off' dystonia in PD, which also results from chronic DA deprivation combined with (mal)adaptive postsynaptic responses.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Sensorimotor Integration Study Section (SMI)
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Sieber, Beth-Anne
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Emory University
Schools of Medicine
United States
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Jinnah, H A; Hess, Ellen J (2018) Evolving concepts in the pathogenesis of dystonia. Parkinsonism Relat Disord 46 Suppl 1:S62-S65
Fan, Xueliang; Donsante, Yuping; Jinnah, H A et al. (2018) Dopamine Receptor Agonist Treatment of Idiopathic Dystonia: A Reappraisal in Humans and Mice. J Pharmacol Exp Ther 365:20-26
Yalcin-Cakmakli, Gul; Rose, Samuel J; Villalba, Rosa M et al. (2018) Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia. Front Syst Neurosci 12:28
Di Ciano, Patricia; Manvich, Daniel F; Pushparaj, Abhiram et al. (2018) Effects of disulfiram on choice behavior in a rodent gambling task: association with catecholamine levels. Psychopharmacology (Berl) 235:23-35
Shakkottai, Vikram G; Batla, Amit; Bhatia, Kailash et al. (2017) Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia. Cerebellum 16:577-594
Jinnah, H A; Neychev, Vladimir; Hess, Ellen J (2017) The Anatomical Basis for Dystonia: The Motor Network Model. Tremor Other Hyperkinet Mov (N Y) 7:506
Rose, Samuel J; Harrast, Porter; Donsante, Christine et al. (2017) Parkinsonism without dopamine neuron degeneration in aged l-dopa-responsive dystonia knockin mice. Mov Disord 32:1694-1700
Rose, Samuel J; Hess, Ellen J (2016) A commentary on the utility of a new L-DOPA-responsive dystonia mouse model. Rare Dis 4:e1128617
Rose, Samuel J; Yu, Xin Y; Heinzer, Ann K et al. (2015) A new knock-in mouse model of l-DOPA-responsive dystonia. Brain 138:2987-3002