Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome
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
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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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 2

Ube3am–/p+ mice exhibit normal BSR threshold responses to cocaine and selective D1 and D2 dopamine receptor antagonists but decreased sensitivity to D2-dependent motor impairment.

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Ube3am–/p+ mice exhibit normal BSR threshold responses to cocaine and s...
BSR threshold was determined following i.p. administration of (A–C) cocaine, (D) the D1 receptor antagonist SCH 23390, or the D2-selective antagonists (E) raclopride or (F) L741,626. (A–C) Cocaine had similar potency on BSR threshold in both genotypes at its peak effect (0–15 minutes), but its rewarding effects decayed more slowly in Ube3am–/p+ mice (46–60 minutes, 10.0 mg/kg, *P = 0.025; 17.0 mg/kg, #P < 0.001). (D) The D1 antagonist SCH 23390, (E) the D2-like antagonist raclopride, or (F) the highly D2-selective antagonist L741,626 equally elevated reward thresholds of WT and mutant mice. (G) However, while D1 receptor antagonism had similar depressant effects on maximum operant response rates of both genotypes, antagonism of D2 receptors with either (H) raclopride (0.178 mg/kg, **P = 0.005; 0.3 mg/kg, #P < 0.001) or (I) L741,626 (5.6 mg/kg, #P < 0.001) had greater depressant effects on maximum response rates of WT mice. Error bars indicate ± SEM.