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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 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

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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 1

UBE3A is highly expressed in the cerebellum.

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UBE3A is highly expressed in the cerebellum.
(A) Western blot analysis r...
(A) Western blot analysis revealed high UBE3A expression levels in the cerebellum of mice and humans. Cortical samples of the same protein concentration were used as a reference. UBE3A protein was greatly reduced in AS mice and in AS patients, indicating that UBE3A expression was almost exclusively derived from the maternal allele in cerebellar neurons. The Western blot shown is representative of samples run in duplicate. (B) UBE3A IHC in the cerebellum of WT mice revealed robust labeling of Purkinje cells (in the Purkinje cell layer [PCL]) and sparsely labeled cells within the molecular layer (ML). High expression levels were also observed in sparsely labeled cells in the granule cell layer (GCL) (white arrows), indicative of Golgi cell labeling. (C) UBE3A immunofluorescence (red, middle panel) colocalized with GlyT2-EGFP expression (green, top panel) in sparsely labeled cells in the granule cell layer, identifying them as Golgi cells. Each staining was performed using a minimum of 3 mice. Scale bars: 5 mm (B, top panels), 1 mm (B, bottom left panels), 0.05 mm (B, bottom right panels, and C).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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