The schizophrenia risk gene product miR-137 alters presynaptic plasticity
Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorph...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2016
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| Online Access: | http://hdl.handle.net/1721.1/102680 https://orcid.org/0000-0002-2206-2590 https://orcid.org/0000-0003-1262-0592 https://orcid.org/0000-0001-8635-0877 https://orcid.org/0000-0002-6335-9681 |
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| author | Siegert, Sandra Seo, Jinsoo Kwon, Ester Rudenko, Andrii Cho, Sukhee Wang, Wenyuan Flood, Zachary Martorell, Anthony Ericsson, Maria Mungenast, Alison Tsai, Li-Huei |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Siegert, Sandra Seo, Jinsoo Kwon, Ester Rudenko, Andrii Cho, Sukhee Wang, Wenyuan Flood, Zachary Martorell, Anthony Ericsson, Maria Mungenast, Alison Tsai, Li-Huei |
| author_sort | Siegert, Sandra |
| collection | MIT |
| description | Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele–carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus. |
| first_indexed | 2024-09-23T09:15:20Z |
| format | Article |
| id | mit-1721.1/102680 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:15:20Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1026802022-09-26T11:08:40Z The schizophrenia risk gene product miR-137 alters presynaptic plasticity Siegert, Sandra Seo, Jinsoo Kwon, Ester Rudenko, Andrii Cho, Sukhee Wang, Wenyuan Flood, Zachary Martorell, Anthony Ericsson, Maria Mungenast, Alison Tsai, Li-Huei Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Siegert, Sandra Seo, Jinsoo Kwon, Ester Rudenko, Andrii Cho, Sukhee Wang, Wenyuan Flood, Zachary Martorell, Anthony Mungenast, Alison Tsai, Li-Huei Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele–carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus. 2016-05-25T17:44:04Z 2016-05-25T17:44:04Z 2015-05 2015-02 Article http://purl.org/eprint/type/JournalArticle 1097-6256 1546-1726 http://hdl.handle.net/1721.1/102680 Siegert, Sandra, Jinsoo Seo, Ester J Kwon, Andrii Rudenko, Sukhee Cho, Wenyuan Wang, Zachary Flood, et al. “The Schizophrenia Risk Gene Product miR-137 Alters Presynaptic Plasticity.” Nat Neurosci 18, no. 7 (May 25, 2015): 1008–1016. https://orcid.org/0000-0002-2206-2590 https://orcid.org/0000-0003-1262-0592 https://orcid.org/0000-0001-8635-0877 https://orcid.org/0000-0002-6335-9681 en_US http://dx.doi.org/10.1038/nn.4023 Nature Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Siegert, Sandra Seo, Jinsoo Kwon, Ester Rudenko, Andrii Cho, Sukhee Wang, Wenyuan Flood, Zachary Martorell, Anthony Ericsson, Maria Mungenast, Alison Tsai, Li-Huei The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title | The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title_full | The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title_fullStr | The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title_full_unstemmed | The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title_short | The schizophrenia risk gene product miR-137 alters presynaptic plasticity |
| title_sort | schizophrenia risk gene product mir 137 alters presynaptic plasticity |
| url | http://hdl.handle.net/1721.1/102680 https://orcid.org/0000-0002-2206-2590 https://orcid.org/0000-0003-1262-0592 https://orcid.org/0000-0001-8635-0877 https://orcid.org/0000-0002-6335-9681 |
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