| Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. | |
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MedLine Citation:
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PMID: 23143301 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (L-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS model mice lacking maternal Ube3a (Ube3a(m-/p+) mice) exhibit behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, Ube3a(m-/p+) mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of L-DOPA therapy in patients with AS. |
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Authors:
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Thorfinn T Riday; Elyse C Dankoski; Michael C Krouse; Eric W Fish; Paul L Walsh; Ji Eun Han; Clyde W Hodge; R Mark Wightman; Benjamin D Philpot; C J Malanga |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-12 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-03 Completed Date: 2013-02-04 Revised Date: 2013-02-27 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4544-54 Citation Subset: AIM; IM |
Affiliation:
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Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina North Carolina 27599, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angelman Syndrome
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metabolism*,
pathology Animals Benzazepines / pharmacology Cocaine / pharmacology Disease Models, Animal Dopamine / metabolism, physiology* Dopamine Uptake Inhibitors / pharmacology Dopaminergic Neurons / drug effects, metabolism* Electric Stimulation Female Indoles / pharmacology Male Mice Mice, Inbred C57BL Motor Activity / drug effects Piperidines / pharmacology Raclopride / pharmacology Receptors, Dopamine D1 / antagonists & inhibitors Receptors, Dopamine D2 / antagonists & inhibitors Reward Self Stimulation Substantia Nigra / metabolism, pathology Synaptic Transmission* Ubiquitin-Protein Ligases / genetics, metabolism Ventral Tegmental Area / metabolism, pathology |
| Grant Support | |
ID/Acronym/Agency:
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AA 011605/AA/NIAAA NIH HHS; AA 014983/AA/NIAAA NIH HHS; AA 018335/AA/NIAAA NIH HHS; AS2670//Autism Speaks; DA 010900/DA/NIDA NIH HHS; MH 093372/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzazepines; 0/Dopamine Uptake Inhibitors; 0/Indoles; 0/Piperidines; 0/Receptors, Dopamine D1; 0/Receptors, Dopamine D2; 0/SCH 23390; 50-36-2/Cocaine; 81226-60-0/3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; 84225-95-6/Raclopride; EC 6.3.2.19/Ube3a protein, mouse; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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