β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome
Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG–binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormal...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2015
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| Online Access: | http://hdl.handle.net/1721.1/93783 https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-9403-8787 https://orcid.org/0000-0002-3551-1244 |
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| author | Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo Crawford, Benjamin Sharma, Jitendra Sheridan, Steven Sur, Mriganka Haggarty, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo Crawford, Benjamin Sharma, Jitendra Sheridan, Steven Sur, Mriganka Haggarty, Stephen J. |
| author_sort | Mellios, Nikolaos |
| collection | MIT |
| description | Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG–binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2−/y) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2−/+) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2−/y mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder. |
| first_indexed | 2024-09-23T08:17:22Z |
| format | Article |
| id | mit-1721.1/93783 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:17:22Z |
| publishDate | 2015 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/937832022-09-30T08:48:45Z β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo Crawford, Benjamin Sharma, Jitendra Sheridan, Steven Sur, Mriganka Haggarty, Stephen J. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Research Laboratory of Electronics Picower Institute for Learning and Memory Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo Crawford, Benjamin Sharma, Jitendra Sheridan, Steven Sur, Mriganka Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG–binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2−/y) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2−/+) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2−/y mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder. National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (Postdoctoral Fellowship 5F32EY020066-03) National Institutes of Health (U.S.) (Grant MH085802) Simons Foundation 2015-02-05T16:15:26Z 2015-02-05T16:15:26Z 2014-06 2013-06 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/93783 Mellios, Nikolaos, Jonathan Woodson, Rodrigo I. Garcia, Benjamin Crawford, Jitendra Sharma, Steven D. Sheridan, Stephen J. Haggarty, and Mriganka Sur. “ β2-Adrenergic Receptor Agonist Ameliorates Phenotypes and Corrects microRNA-Mediated IGF1 Deficits in a Mouse Model of Rett Syndrome.” Proceedings of the National Academy of Sciences 111, no. 27 (June 23, 2014): 9947–9952. https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-9403-8787 https://orcid.org/0000-0002-3551-1244 en_US http://dx.doi.org/10.1073/pnas.1309426111 Proceedings of the National Academy of Sciences of the United States of America 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 National Academy of Sciences (U.S.) National Academy of Sciences (U.S.) |
| spellingShingle | Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo Crawford, Benjamin Sharma, Jitendra Sheridan, Steven Sur, Mriganka Haggarty, Stephen J. β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title | β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title_full | β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title_fullStr | β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title_full_unstemmed | β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title_short | β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome |
| title_sort | β2 adrenergic receptor agonist ameliorates phenotypes and corrects microrna mediated igf1 deficits in a mouse model of rett syndrome |
| url | http://hdl.handle.net/1721.1/93783 https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-9403-8787 https://orcid.org/0000-0002-3551-1244 |
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