Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model
Caroline F. Bruinsma, … , Chris I. De Zeeuw, Ype Elgersma
Caroline F. Bruinsma, … , Chris I. De Zeeuw, Ype Elgersma
Published November 2, 2015; First published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4305-4315. https://doi.org/10.1172/JCI83541.
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Research Article Neuroscience

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Abstract

Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3am–/p+ mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phase-reversal learning nor locomotion was impaired following selective deletion of Ube3a in Purkinje cells. However, genetic normalization of αCaMKII inhibitory phosphorylation fully rescued locomotor deficits despite failing to improve cerebellar learning in AS mice, suggesting extracerebellar circuit involvement in locomotor learning. We confirmed this hypothesis through cerebellum-specific reinstatement of Ube3a, which ameliorated cerebellar learning deficits but did not rescue locomotor deficits. This double dissociation of locomotion and cerebellar phenotypes strongly suggests that the locomotor deficits of AS mice do not arise from impaired cerebellar cortex function. Our results provide important insights into the etiology of the motor deficits associated with AS.

Authors

Caroline F. Bruinsma, Martijn Schonewille, Zhenyu Gao, Eleonora M.A. Aronica, Matthew C. Judson, Benjamin D. Philpot, Freek E. Hoebeek, Geeske M. van Woerden, Chris I. De Zeeuw, Ype Elgersma

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Figure 7

Cerebellar reinstatement of UBE3A expression rescues cerebellar learning but not rotarod learning.

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Cerebellar reinstatement of UBE3A expression rescues cerebellar learning...
(A) Rotarod learning for Ube3aStop/p+ CreERT+ mice was impaired compared with that of Ube3am+/p+ CreERT+ control (WT) mice. The y axis indicates the time the mice stayed on the rotarod before falling off. (B) VOR gain decrease for Ube3aStop/p+ CreERT+ and control (WT) mice during a 50-minute training period on day 1 as well as the consolidation test on day 2. No differences were observed between the genotypes. (C) Ube3aStop/p+ CreERT+ mice showed no differences in VOR phase-reversal learning compared with control (WT) mice. Following the VOR gain decrease shown in B, the mice were further trained by rotating them at a 5° amplitude while the surrounding screen was rotated at a 7.5° amplitude (day 2) and a 10° amplitude (days 3 and 4), in the same direction, to induce VOR phase reversal. For all experiments, 7 mice of each genotype were used. *P < 0.05, as determined by a repeated-measures ANOVA, followed by a post-hoc Bonferroni test. Error bars indicate the SEM.