UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

Sun, Jiandong; Zhu, Guoqi; Liu, Yan; Standley, Steve; Ji, Angela; Tunuguntla, Rashmi; Wang, Yubin; Claus, Chad F; Luo, Yun; Baudry, Michel; Bi, Xiaoning

doi:10.1016/j.celrep.2015.06.023

Cited by 106 publications

(141 citation statements)

References 55 publications

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“…In addition to behavioral flexibility, the autism genes in our study participate in some other cognitive processes such as learning and long-term memory (29,33,69,70). For instance, as a general translational repressor, Fmr1 interacts with Staufen and the RNAi pathway to regulate long-term memory formation.…”

Section: Discussionmentioning

confidence: 99%

“…Fmr1 encodes an RNA-binding protein that regulates translation and has been extensively characterized in Drosophila for its role in synaptic signaling and long-term memory formation (29,30). Ube3a encodes a ubiquitin ligase that has functions in learning and memory, synapse development, and synaptic plasticity (31)(32)(33)(34). Importantly, Drosophila Ube3a (dUbe3a) is highly homologous to human Ube3a (hUbe3a) (34).…”

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confidence: 99%

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Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.A utism spectrum disorders are common polygenic neurodevelopmental disorders diagnosed by a cluster of core clinical syndromes characterized by impaired social interaction, communication deficits, and behavioral inflexibility (1-3). A large number of autism-risk genes have been identified through different genetic approaches (4-8). These candidate genes play highly diversified roles in synaptic organization, transmission, intracellular signaling pathways, and protein expression regulation, among others (9). How do variants of these risk genes lead to the core symptoms of autism? Are there causal paths that can determine the onset of autism? Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10-13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14-16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.The aim of the this study was to determine whether Rac1 (Rasrelated C3 botulinum toxin substrate 1)-dependent forgetting is a functional converging point for autism-risk genes. This idea was inspired by two clues. First, inhibition of Rac1 activity in Drosophila leads to the failure to activate Rac1-dependent forgetting, resulting in behavioral inflexibility as assayed through a reversal-learning task (20). Behavioral inflexibility has been observed frequently in the clinical studies of autism patients (21,22), and children with autism are reported to have impaired reversal-learning, although they can learn new beh...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The excitatory neurotransmission was decreased in neocortex and hippocampal CA1 region (Greer et al 2010; Kaphzan et al 2011; Wallace et al 2012; Yashiro et al 2009). The increased SK2 potassium channel levels for after-hyperpolarization in Ube3a m − /p + might suggest a decrease of excitability as well (Sun et al 2015). Interestingly, GABAergic neuron specific loss of Ube3a results in abnormal EEG and enhanced seizure susceptibility (Judson et al 2016; Santini and Klann 2016).…”

Section: Introductionmentioning

confidence: 99%

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

Chung

Bey

Towers

et al. 2018

Neurobiology of Disease

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Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3am−/p+) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3am−/p+ in vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3am−/p+. The in vitro model of Ube3am−/p+ is valuable for dissection of neural mechanism and epilepsy drug screening in vivo.

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“…Finally, a recent study reports that transcripts encoding the E3 ubiquitin ligase UBE3A have a non-coding role in dendrite growth and spine maturation in hippocampal neurons; by contrast, UBE3A protein plays crucial roles in activity-dependent synapse development, plasticity, learning and memory (Sun et al, 2015;Valluy et al, 2015). This role was discovered using antisense short hairpin RNAs (shRNAs) that target Ube3a 3′UTR variants in rat hippocampal neurons: the neurons showed significantly increased dendrite growth and complexity upon knockdown of the non-translated and intron-retaining Ube3a1 RNA, whereas shRNAs targeting the spliced coding Ube3a2/3 isoforms reduced dendrite complexity (Valluy et al, 2015).…”

Section: Ube3amentioning

confidence: 99%

CncRNAs: RNAs with both coding and non-coding roles in development

Sampath

Ephrussi

2016

Development

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RNAs are known to regulate diverse biological processes, either as protein-encoding molecules or as non-coding RNAs. However, a third class that comprises RNAs endowed with both protein coding and non-coding functions has recently emerged. Such bi-functional 'coding and non-coding RNAs' (cncRNAs) have been shown to play important roles in distinct developmental processes in plants and animals. Here, we discuss key examples of cncRNAs and review their roles, regulation and mechanisms of action during development.

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UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

Cited by 106 publications

References 55 publications

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

CncRNAs: RNAs with both coding and non-coding roles in development

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