Dataset Information

Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

ABSTRACT: Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson's disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin(-/-)) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. Behaviorally, Dorfin(-/-) mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin(-/-) brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory.

SUBMITTER: Park H

PROVIDER: S-EPMC4639748 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

Park Hanwool H Yang Jinhee J Kim Ryunhee R Li Yan Y Lee Yeunkum Y Lee Chungwoo C Park Jongil J Lee Dongmin D Kim Hyun H Kim Eunjoon E

Scientific reports 20151110

Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson's disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin(-/-)) mice show reduced adult neurogenesis and enhanced long-term poten ...[more]

PMID: 26553645

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Project description:A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Many neurological, psychiatric and neurodevelopmental disorders are associated with cognitive deficits. Therefore characterizing the biological basis of these processes is critical for understanding normal and abnormal brain function. It is known that long-term memory formation requires transcription and translation as well as epigenetic processes that control gene expression. In this study we examined genome-wide gene expression changes during memory consolidation and after memory retrieval. We observe the largest changes in gene expression 30 minutes after memory acquisition and retrieval, and several novel genes were found to be affected by both. Interestingly, acquisition and retrieval of memory down-regulate different processes. Chromatin assembly is down-regulated after memory acquisition whereas RNA processing is down-regulated so after retrieval. Histone variant H2AB levels are reduced following acquisition, while splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR-219 are down-regulated following retrieval. We also show that miR-219 down-regulation after retrieval is accompanied by up-regulation of its target protein CAMKIIÎ³. Our study highlights for the first time the differential involvement of epigenetic mechanisms that control gene expression, such as histone variants and post-transcriptional RNA processing, during memory acquisition and retrieval. 72 total samples were analyzed, including animals trained in a contexual conditioning paradigm (FC) and controls. Tissue was collected at 30 minutes (FC30), 4 hours (FC4), 12 hours (FC12) and 24 hours after FC (FC24) as well as 30 minutes after testing for retrieval of the memory (RT30). Testing was performed at 24 hours after training over a 5-minute interval. Animals that were handled but not trained were dissected at the same time of day to control for variations due to circadian rhythms (CC30, CC4 andCC12). The protocol was repeated over the course of 2 weeks to obtain 9 animals (2 hippocampi) per group, so that 9 independent FC experiments were represented in each time point and all animals for each group were dissected at the exactly the same time of day.

Dataset Information

Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

Publications

Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

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