Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS
Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Oxford University Press
2016
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| Online Access: | http://hdl.handle.net/1721.1/102350 https://orcid.org/0000-0003-0582-2284 |
| _version_ | 1826194294698934272 |
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| author | Till, Sally M. Asiminas, Antonis Jackson, Adam D. Katsanevaki, Danai Barnes, Stephanie A. Chattarji, Sumantra Wood, Emma R. Kind, Peter C. Osterweil, Emily Bear, Mark Wyllie, David J. A. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Till, Sally M. Asiminas, Antonis Jackson, Adam D. Katsanevaki, Danai Barnes, Stephanie A. Chattarji, Sumantra Wood, Emma R. Kind, Peter C. Osterweil, Emily Bear, Mark Wyllie, David J. A. |
| author_sort | Till, Sally M. |
| collection | MIT |
| description | Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory. |
| first_indexed | 2024-09-23T09:53:50Z |
| format | Article |
| id | mit-1721.1/102350 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:53:50Z |
| publishDate | 2016 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | mit-1721.1/1023502022-09-30T17:34:03Z Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS Till, Sally M. Asiminas, Antonis Jackson, Adam D. Katsanevaki, Danai Barnes, Stephanie A. Chattarji, Sumantra Wood, Emma R. Kind, Peter C. Osterweil, Emily Bear, Mark Wyllie, David J. A. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Osterweil, Emily Bear, Mark Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory. 2016-05-02T15:26:52Z 2016-05-02T15:26:52Z 2015-11 2015-07 Article http://purl.org/eprint/type/JournalArticle 0964-6906 1460-2083 http://hdl.handle.net/1721.1/102350 Till, Sally M., Antonis Asiminas, Adam D. Jackson, Danai Katsanevaki, Stephanie A. Barnes, Emily K. Osterweil, Mark F. Bear, et al. “Conserved Hippocampal Cellular Pathophysiology but Distinct Behavioural Deficits in a New Rat Model of FXS.” Human Molecular Genetics 24, no. 21 (August 4, 2015): 5977–5984. https://orcid.org/0000-0003-0582-2284 en_US http://dx.doi.org/10.1093/hmg/ddv299 Human Molecular Genetics Creative Commons Attribution Non-Commercial License http://creativecommons.org/licenses/by-nc/4.0/ application/pdf Oxford University Press Oxford University Press |
| spellingShingle | Till, Sally M. Asiminas, Antonis Jackson, Adam D. Katsanevaki, Danai Barnes, Stephanie A. Chattarji, Sumantra Wood, Emma R. Kind, Peter C. Osterweil, Emily Bear, Mark Wyllie, David J. A. Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title | Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title_full | Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title_fullStr | Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title_full_unstemmed | Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title_short | Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS |
| title_sort | conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of fxs |
| url | http://hdl.handle.net/1721.1/102350 https://orcid.org/0000-0003-0582-2284 |
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