Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model.
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.
Caroline F
CF
Bruinsma
Martijn
M
Schonewille
Zhenyu
Z
Gao
Eleonora M A
EM
Aronica
Matthew C
MC
Judson
Benjamin D
BD
Philpot
Freek E
FE
Hoebeek
Geeske M
GM
van Woerden
Chris I
CI
De Zeeuw
Ype
Y
Elgersma
D017204:Angelman Syndrome / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D002531:Cerebellum / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics / Q000503:physiopathology; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology; D012027:Reflex, Vestibulo-Ocular; D045442:Rotarod Performance Test; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics
C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2