SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION
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Case Western Reserve University School of Graduate Studies / OhioLINK
2021
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ndltd-OhioLink-oai-etd.ohiolink.edu-case1600954815369062021-08-03T07:16:22Z SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION Dong, Zhaoqi Neurosciences Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with symptoms, including social deficits, anxiety, and communication difficulties. However, ASD pathogenic mechanisms are poorly understood. Mutations of CUL3, which encodes Cullin 3 (CUL3), a component of an E3 ligase complex, are thought of as risk factors for ASD and schizophrenia (SCZ). CUL3 is abundant in the brain, yet little is known of its function. My work showed that CUL3 is critical for neurodevelopment. Moreover, CUL3 deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability similar to pathological conditions observed in ASD patients. Furthermore, proteomic analysis or the cortical tissue revealed differences in a group of proteins. With biochemical analysis, the expression level of various proteins was found to be increased. From which, eIF4G1, a protein for Cap-dependent translation, was found to be a potential target of CUL3. We have also demonstrated that ASD-associated cellular and behavioral deficits could be mitigated by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity. Besides, dysregulated neuronal connectivity revealed by impaired theta synchrony was observed in CUL3 deficient mice during the social novelty recognition test. Interestingly, inhibition of CUL3 by a specific inhibitor, DI-591, promoted glutamatergic transmission, and inhibited NSF ubiquitination. Thus, CUL3 is critical to neural development, neurotransmission, circuitry connections, and which helps to maintain normal behavioral functions. Our research revealed novel insight into the pathophysiological mechanisms of ASD. 2021-01-22 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case160095481536906 http://rave.ohiolink.edu/etdc/view?acc_num=case160095481536906 restricted--full text unavailable until 2023-01-15 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
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English |
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NDLTD |
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Neurosciences |
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Neurosciences Dong, Zhaoqi SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| author |
Dong, Zhaoqi |
| author_facet |
Dong, Zhaoqi |
| author_sort |
Dong, Zhaoqi |
| title |
SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| title_short |
SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| title_full |
SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| title_fullStr |
SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| title_full_unstemmed |
SYNAPTIC, CIRCUITRY AND BEHAVIORAL DEFICITS INDUCED BY AUTISM SPECTRUM DISORDER ASSOCIATED CULLIN3 MUTATION |
| title_sort |
synaptic, circuitry and behavioral deficits induced by autism spectrum disorder associated cullin3 mutation |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2021 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case160095481536906 |
| work_keys_str_mv |
AT dongzhaoqi synapticcircuitryandbehavioraldeficitsinducedbyautismspectrumdisorderassociatedcullin3mutation |
| _version_ |
1719457887031394304 |