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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 Ube3α^sup m-/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 Ube3α 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 Ube3α, 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.
Introduction
Angelman syndrome (AS) is a neurological genetic imprinting disorder caused by mutations affecting the maternally inherited UBE3A gene, which encodes the E3A ubiquitin protein ligase (UBE3A or E6-AP). Individuals with AS suffer from severe developmental delay, cognitive deficits, epilepsy, and a lack of speech (1). Individuals with AS also experience problems with movement and balance, an important aspect of the diagnostic criteria described in the original description of the disorder (2). Even in the least severe cases, forward lurching, unsteadiness, jerky motions, and tremulous movement of limbs may manifest (1). The locus of these motor abnormalities is currently unknown, but it is possible that cerebellar dysfunction is a causal factor, given that ataxia and tremor are both common symptoms of cerebellar disorders. In support of this hypothesis, GABAA receptors have been shown to be reduced in the cerebellum of patients with AS and in postmortem AS material (3-5). Furthermore, movement studies in patients with AS showed abnormal electromyographic (EMG) rhythmic bursts when maintaining posture (6), which could be indicative of...