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Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders.

ABSTRACT: The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.

SUBMITTER: Xu X

PROVIDER: S-EPMC5752837 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders.

Xu Xingxing X Li Chuanyin C Gao Xiaobo X Xia Kun K Guo Hui H Li Yali Y Hao Zijian Z Zhang Lei L Gao Daming D Xu Chenfan C Xu Huatai H Xiong Zhi-Qi ZQ Qiu Zilong Z Mei Ling L Xie Xiaoduo X Ruan Kangcheng K Hu Ronggui R

Cell research 20171027 1

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. ...[more]

PMID: 29076503

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Project description:The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders.Significance statementA genetic overlap exists between autism spectrum disorders (ASD), currently thought to represent a continuum of the same disorder with varying degrees of severity, and other neurodevelopmental and neuropsychiatric endophenotypes. We show that the duplication of a single gene coding for a high-affinity kainate receptor subunit (i.e., grik4) in a limited area of the brain recapitulates behavioral endophenotypes seen in humans diagnosed with autism (anhedonia, depression, anxiety, and altered social interaction), including some humans with GRIK4 duplications. Therefore, it should be possible to use mice overexpressing grik4 to directly address circuit dysfunctions associated with ASDs and test specific treatments of autism-related behaviors.

Project description:The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into socio-communicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying socio-communicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

Dataset Information

Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders.

Publications

Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders.

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