title: A new knock-in mouse model of l-DOPA-responsive dystonia.
abstract: Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotransmission in dystonia, the precise nature of the pre- and postsynaptic defects that result in dystonia are not known. To better understand these defects, we generated a knock-in mouse model of l-DOPA-responsive dystonia (DRD) mice that recapitulates the human p.381Q>K TH mutation (c.1141C>A). Mice homozygous for this mutation displayed the core features of the human disorder, including reduced TH activity, dystonia that worsened throughout the course of the active phase, and improvement in the dystonia in response to both l-DOPA and trihexyphenidyl. Although the gross anatomy of the nigrostriatal dopaminergic neurons was normal in DRD mice, the microstructure of striatal synapses was affected whereby the ratio of axo-spinous to axo-dendritic corticostriatal synaptic contacts was reduced. Microinjection of l-DOPA directly into the striatum ameliorated the dystonic movements but cerebellar microinjections of l-DOPA had no effect. Surprisingly, the striatal dopamine concentration was reduced to ∼1% of normal, a concentration more typically associated with akinesia, suggesting that (mal)adaptive postsynaptic responses may also play a role in the development of dystonia. Administration of D1- or D2-like dopamine receptor agonists to enhance dopamine signalling reduced the dystonic movements, whereas administration of D1- or D2-like dopamine receptor antagonists to further reduce dopamine signalling worsened the dystonia, suggesting that both receptors mediate the abnormal movements. Further, D1-dopamine receptors were supersensitive; adenylate cyclase activity, locomotor activity and stereotypy were exaggerated in DRD mice in response to the D1-dopamine receptor agonist SKF 81297. D2-dopamine receptors exhibited a change in the valence in DRD mice with an increase in adenylate cyclase activity and blunted behavioural responses after challenge with the D2-dopamine receptor agonist quinpirole. Together, our findings suggest that the development of dystonia may depend on a reduction in dopamine in combination with specific abnormal receptor responses.
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Rose
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xin Y
authors.initials: XY
authors.lastname: Yu
authors.affiliation: 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Heinzer
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Porter
authors.initials: P
authors.lastname: Harrast
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xueliang
authors.initials: X
authors.lastname: Fan
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Raike
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: Thompson
authors.affiliation: 3 Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA 4 Udall Center of Excellence for Parkinson's Disease, Emory University, Atlanta, GA 30329, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pare
authors.affiliation: 5 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.affiliation: 3 Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA 4 Udall Center of Excellence for Parkinson's Disease, Emory University, Atlanta, GA 30329, USA 6 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.affiliation: 5 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA 6 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA 7 Department of Pediatrics Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hyder A
authors.initials: HA
authors.lastname: Jinnah
authors.affiliation: 1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA 6 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA ellen.hess@emory.edu.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hess
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002395:Catecholamines / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004421:Dystonia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011877:Radionuclide Imaging; D013239:Stereotyped Behavior / Q000502:physiology; D014316:Tritium / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D001552:Benzazepines; D002395:Catecholamines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; C534628:SCH 23390; D014316:Tritium; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase
keywords: corticostriatal; dopamine; striatum; trihexyphenidyl; tyrosine hydroxylase