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.
View: Text | PDF
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

×

Figure 1

Ube3am–/p+ mice are more sensitive to BSR but less sensitive to dopaminergic potentiation of BSR.

Options: View larger image (or click on image) Download as PowerPoint
Ube3am–/p+ mice are more sensitive to BSR but less sensitive to dopamin...
(A) Representative ICSS rate-frequency curves in a WT mouse. Injection (i.p.) of the DAT antagonist GBR 12909 dose-dependently increases responding for rewarding electrical current at lower stimulus frequencies. (B) Rate-frequency curves expressed as charge (Q) delivery at each frequency (Hz) from Ube3am–/p+ mice are shifted to the left compared with those of WT littermates. (C) Ube3am–/p+ mice require significantly less (***P < 0.001) charge to evoke the same degree of responding as WT mice at reward threshold frequencies (EF50). (D) The maximum rate of operant responding for rewarding brain stimulation is comparable between genotypes (P > 0.05). (E) Ube3am–/p+ mice maintain a lower reward threshold over time (16–30 minutes, ***P < 0.001; 31–45 minutes, ***P < 0.001; 46–60 minutes, *P = 0.026). (F) WT mice exhibit greater potentiation of rewarding brain stimulation expressed as lower reward thresholds than Ube3am–/p+ mice following 10.0 mg/kg (**P = 0.002) and 17.0 mg/kg (***P < 0.001) GBR 12909 (i.p.). Error bars indicate ± SEM in B, E, and F and the median and interquartile ranges in C and D.