Extra-cerebellar motor symptoms in Angelman’s syndrome
Angelman’s syndrome (AS) is a severe neurological disorder that is characterized by a range of neurobehavioral deficits, including motor and balance impairments. Mutations that silence the maternally imprinted UBE3A gene underlie AS, although little is known regarding the neural circuit-level dysfunction that mediates AS symptoms. Ataxia and tremor are present in both AS and cerebellar disorders, supporting the hypothesis that AS motor impairments are cerebellar in origin. However, no direct testing of this hypothesis has previously been performed. Caroline Bruinsma and colleagues at the Erasmus University Medical Center measured cerebellum-dependent visual motor learning in a genetic mouse model of AS. AS mice displayed locomotor impairments and mild deficits in cerebellum-dependent learning, as measured by the vestibular-ocular reflex phase-reversal test. Electrophysiological examinations of cerebellar circuitry in these mice revealed impaired tonic inhibition of granule cells, despite normal Purkinje cell physiology, thereby establishing a potential neurobiological correlate to the observed behavioral deficits. As it is unclear whether cerebellar learning deficits and locomotor impairments in AS mice both result from loss of cerebellar UBE3A expression, the authors developed an AS model in which UBE3A expression was partially restored in cerebellum but remained absent in the forebrain. These mice displayed normal cerebellar-dependent learning but impaired locomotion, suggesting that locomotor deficits in AS are likely mediated by UBE3A loss outside the cerebellum. The accompanying image shows UBE3A expression (brown) in the cerebellum of WT (left) mice and in animals with Purkinje cell-specific loss of UBE3A (right). In WT animals, UBE3A expression (brown) is distinct within the Purkinje cell layer and completely absent in these cells of mutant mice. Lack of UBE3A in Purkinje cells does not affect cerebellar learning.
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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
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
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)