title: Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.
abstract: 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.
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Till
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors.forename: Antonis
authors.initials: A
authors.lastname: Asiminas
authors.affiliation: Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Jackson
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Danai
authors.initials: D
authors.lastname: Katsanevaki
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Barnes
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK, Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge MA 02139, USA and.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Osterweil
authors.affiliation: Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge MA 02139, USA and.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Bear
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India.
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chattarji
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Wood
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.affiliation: Patrick Wild Centre, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Integrative Physiology, The University of Edinburgh, Edinburgh EH8 9XD, UK, Centre for Brain Development and Repair, The Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India, pkind@ed.ac.uk.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D009473:Neuronal Plasticity; D017966:Pyramidal Cells / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497685:Fmr1 protein, rat