Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome
Thorfinn T. Riday, … , Benjamin D. Philpot, C.J. Malanga
Thorfinn T. Riday, … , Benjamin D. Philpot, C.J. Malanga
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4544-4554. https://doi.org/10.1172/JCI61888.
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Research Article Neuroscience

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

Abstract

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 (Ube3am–/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, Ube3am–/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.

Authors

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

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Figure 4

Biochemical and anatomical markers of the mesolimbic and nigrostriatal dopaminergic pathways are normal in Ube3am–/p+ mice.

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Biochemical and anatomical markers of the mesolimbic and nigrostriatal d...
(A) Immunohistochemistry showing imprinting of UBE3A in the mesencephalic VTA and SNc and colocalization with TH in WT mice (original magnification, ×4). Boxed regions are shown at higher magnification in the second, third, and fourth columns (original magnification, ×40). (B) Numbers of TH-positive cells in the VTA and SNc estimated with design-based stereology show no differences between WT and Ube3am–/p+ mice. Ventral midbrain image is magnified (original magnification, ×4) and the boxed region is shown at higher magnification to the right (original magnification, ×40). (C) Quantification of TH, the rate-limiting enzyme in dopamine biosynthesis, from NAc and striatal tissue punches by immunoblotting shows similar levels between the 2 genotypes. (D) HPLC analysis of concentrations of dopamine and (E) its primary acid metabolite DOPAC in NAc and striatal punches from WT and Ube3am–/p+ mice shows similar tissue content of dopamine and DOPAC. (F) Dopamine/DOPAC ratios are also equivalent between genotypes in NAc and striatum. Error bars indicate SEM. Numbers in bars represent numbers of mice.