Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Bruinsma, Caroline F.; Schonewille, Martijn; Gao, Zhenyu; Aronica, Eleonora; Judson, Matthew C.; Philpot, Benjamin D.; Hoebeek, Freek E.; Woerden, Geeske M. van; Zeeuw, Chris I. De; Elgersma, Ype

doi:10.1172/jci83541

Cited by 43 publications

(45 citation statements)

References 55 publications

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“…Rotarod motor coordination and balance were significantly impaired in Ube3a mice, consistent with previous reports (Huang et al, 2013; Bruinsma et al, 2015). However, open field exploratory locomotion scores were not significantly different between Ube3a and WT littermate controls.…”

Section: Discussionsupporting

confidence: 93%

“…Rotarod motor coordination and balance were significantly impaired in Ube3a mice, consistent with previous reports. 44,78 However, open field exploratory locomotion scores were not significantly different between Ube3a and WT littermate controls. It is important to note that motor disabilities detected in a genetic mouse model can introduce artifacts that may directly affect performance on cognitive tasks such as water maze.…”

Section: Touchscreen Training In Mecp2 Micementioning

confidence: 87%

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Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Leach

Crawley

2018

Genes Brain and Behavior

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Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2 mouse model of Rett syndrome. Significant deficits in acquisition of a 2-choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics.

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Section: Discussionsupporting

confidence: 93%

Section: Touchscreen Training In Mecp2 Micementioning

confidence: 87%

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Leach

Crawley

2018

Genes Brain and Behavior

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“…A recent report by Elgersma and colleagues using the cerebellar-specific vestibulo-ocular reflex paradigm shows near-normal function of the cerebellum. [67] This observation is in contrast to reports on mTOR signaling deficiency in the cerebellum of the AS mouse model [68] and abnormal Purkinje cell firing rate and rhythmicity in AS mice. [51] There may be multiple sites of dysfunction, or the defect in synaptic function extends beyond the hippocampus to corticalcerebellum communication.…”

Section: Resultscontrasting

confidence: 71%

Towards targeted therapy for Angelman syndrome

Ciarlone

Weeber

2016

Expert Opinion on Orphan Drugs

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Introduction: Angelman syndrome (AS) is a monogenic disorder with a prevalence of 1 in 10-15,000 and is characterized by severe developmental delay, ataxia, and epilepsy. AS is associated with a neuron-specific loss of function of the maternal UBE3A allele, a gene that encodes for a ubiquitin ligase. The null mutation AS mouse model lends well to therapeutic evaluation related to potential treatments for this disorder. Areas covered: This outlook focuses on advances in both pharmacological and molecular therapies that have been explored specifically in the AS mouse model. The utility of the animal model has broadened our current understanding of the disorder and potential therapeutic targets, and provides a better idea of how therapeutics may look in the future as we advance toward clinical trials in this population. Expert opinion: Great advances in all areas of Angelman syndrome research is tempered by requirements to be met at the level of target identification, models of AS, addressing the needs of the AS population, and the clinical trials that will seek their involvement. ARTICLE HISTORY

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“…For example, tonic inhibitory deficits onto cerebellar granule cells in AS mice are linked to impaired locomotion, which is amenable to rescue by the δ-GABA A R superagonist THIP (Gaboxadol) (Egawa et al, 2012). It has since been shown that cerebellar deficits consequent to the loss of tonic GABAergic inhibition onto cerebellar granule cells are clearly dissociable from locomotor defects (Bruinsma et al, 2015), suggesting that any therapeutic benefit of THIP for gross motor dysfunction works through the enhancement of tonic GABAergic inhibition in extracerebellar circuits. Together with our present findings, these studies underscore the need for further preclinical elucidation of a complex relationship between deficits in tonic inhibition and AS-like phenotypes; such knowledge will be essential to inform future clinical trials of THIP administration in AS patients – especially with regard to the selection of appropriate clinical endpoints.…”

Section: Discussionmentioning

confidence: 99%

GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility

Judson

Wallace

Sidorov

et al. 2016

Neuron

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137

131

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SUMMARY Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs) – all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.

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Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

Cited by 43 publications

References 55 publications

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Towards targeted therapy for Angelman syndrome

GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility

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