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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 4

Reduced tonic but not phasic inhibition at the Golgi-to-granule cell synapse in AS mice.

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Reduced tonic but not phasic inhibition at the Golgi-to-granule cell syn...
(A) Left: representative traces of currents recorded from 4-week-old WT and AS mouse granule cells. The amplitude of tonic currents was measured by comparing the holding currents before and after the application of picrotoxin (PTX). Right: summary of tonic currents recorded in WT (n = 10) and AS (n = 15) granule cells. Student’s 2-tailed t tests showed a significant difference (*P < 0.05) in tonic currents. (B) Comparison of sIPSC amplitudes, rise times, and decay times between WT (n = 13) and AS (n = 19) mice using a 2-tailed Student’s t test. Granule cells showed no changes in phasic inhibition. Error bars indicate the SEM. Inset: representative traces of sIPSCs recorded in granule cells from a 4-week-old WT mouse (black) and an AS mouse (red).
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