Document Detail

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome.
MedLine Citation:
PMID:  23143301     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-10-24    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4544-54     Citation Subset:  AIM; IM    
Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina North Carolina 27599, USA.
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MeSH Terms
Angelman Syndrome / metabolism*,  pathology
Benzazepines / pharmacology
Cocaine / pharmacology
Disease Models, Animal
Dopamine / metabolism,  physiology*
Dopamine Uptake Inhibitors / pharmacology
Dopaminergic Neurons / drug effects,  metabolism*
Electric Stimulation
Indoles / pharmacology
Mice, Inbred C57BL
Motor Activity / drug effects
Piperidines / pharmacology
Raclopride / pharmacology
Receptors, Dopamine D1 / antagonists & inhibitors
Receptors, Dopamine D2 / antagonists & inhibitors
Self Stimulation
Substantia Nigra / metabolism,  pathology
Synaptic Transmission*
Ubiquitin-Protein Ligases / genetics,  metabolism
Ventral Tegmental Area / metabolism,  pathology
Grant Support
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; R01 MH093372/MH/NIMH NIH HHS
Reg. No./Substance:
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 protein, mouse; EC Ligases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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