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Cited by 109Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

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Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS

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Till, Sally M., Asiminas, Antonis, Jackson, Adam D., Katsanevaki, Danai, Barnes, Stephanie A., Osterweil, Emily K., Bear, Mark F., Chattarji, Sumantra, Wood, Emma R., Wyllie, David J.A., Kind, Peter C.·2015·Human Molecular Genetics
DOI 10.1093/hmg/ddv299PMC PMC4599667
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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.

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Figure 1. Developmental expression profile of FMRP in rats. Immunohisto-chemical localization of FMRP in P7 (A), P14 (B) and adult (C) WT SD rats. Immunolabelling of a P10 Fmr1 KO shows specificity of antibody for FMRP (D). Western blot analysis of FMRP expression levels in hippocampus homogenates from WT SD rats littermates over postnatal development compared with P10 Fmr1 KO rat (E). Scale bars: (A–C): 500 µm; (D) 250 µm.
Figure 1. Developmental expression profile of FMRP in rats. Immunohisto-chemical localization of FMRP in P7 (A), P14 (B) and adult (C) WT SD rats. Immunolabelling of a P10 Fmr1 KO shows specificity of antibody for FMRP (D). Western blot analysis of FMRP expression levels in hippocampus homogenates from WT SD rats littermates over postnatal development compared with P10 Fmr1 KO rat (E). Scale bars: (A–C): 500 µm; (D) 250 µm.CC BY-NC · PubMed Central
Figure 2. Altered dendritic spine density and shape in the hippocampus of Fmr1 KO rats. An example Alexafluor 568 filled hippocampal CA1 pyramidal neuron (A) and representative apical oblique dendritic segments from WT (B′) and Fmr1 KO rats (B″). (C) Quantification of the density of dendritic protrusions reveals a significant increase on secondary apical obliques in Fmr1 KO rats compared with WT control littermates. In contrast, spine density of secondary basal dendrites is comparable between genotypes. KS-tests of the cumulative frequency distributions indicate differences in the distribution profiles of spine head diameters on apical (D) and basal (E) CA1 dendrites between Fmr1 KO and WT rats. Dotted lines show the cumulative distribution for each animal, solid lines represent group means. The MSHD is not significantly different between genotypes.
Figure 2. Altered dendritic spine density and shape in the hippocampus of Fmr1 KO rats. An example Alexafluor 568 filled hippocampal CA1 pyramidal neuron (A) and representative apical oblique dendritic segments from WT (B′) and Fmr1 KO rats (B″). (C) Quantification of the density of dendritic protrusions reveals a significant increase on secondary apical obliques in Fmr1 KO rats compared with WT control littermates. In contrast, spine density of secondary basal dendrites is comparable between genotypes. KS-tests of the cumulative frequency distributions indicate differences in the distribution profiles of spine head diameters on apical (D) and basal (E) CA1 dendrites between Fmr1 KO and WT rats. Dotted lines show the cumulative distribution for each animal, solid lines represent group means. The MSHD is not significantly different between genotypes.CC BY-NC · PubMed Central
Figure 3. Loss of FMRP alters synaptic plasticity and basal protein synthesis in the rat hippocampus. (A) Sample fEPSP traces from 5 min pre- and 55 min post-DHPG treatment are shown above average fEPSP plots for both WT and Fmr1 KO slices normalized to pre-DHPG baseline. (A) The magnitude of DHPG-induced LTD in WT and Fmr1 KO rats was not significantly different between genotypes. (B) While the persistent expression of mGluR-LTD did not require new protein synthesis in Fmr1 KO rats, mGluR-LTD was not maintained in WT rats in the presence of protein synthesis inhibitor cycloheximide. (C) Basal protein synthesis levels are excessive in dorsal hippocampal slices from Fmr1 KO rats compared with WT littermate controls. Calibration bars for A and B: 0.5 mV, 10 ms.
Figure 3. Loss of FMRP alters synaptic plasticity and basal protein synthesis in the rat hippocampus. (A) Sample fEPSP traces from 5 min pre- and 55 min post-DHPG treatment are shown above average fEPSP plots for both WT and Fmr1 KO slices normalized to pre-DHPG baseline. (A) The magnitude of DHPG-induced LTD in WT and Fmr1 KO rats was not significantly different between genotypes. (B) While the persistent expression of mGluR-LTD did not require new protein synthesis in Fmr1 KO rats, mGluR-LTD was not maintained in WT rats in the presence of protein synthesis inhibitor cycloheximide. (C) Basal protein synthesis levels are excessive in dorsal hippocampal slices from Fmr1 KO rats compared with WT littermate controls. Calibration bars for A and B: 0.5 mV, 10 ms.CC BY-NC · PubMed Central
Figure 4. Fmr1 KO rats have normal spatial reference memory acquisition and reversal learning. (A) Fmr1 KO rats learn the hidden-platform version of the water maze similarly to WT littermates as measured by a decrease over days in the path taken to escape (A) and the number of crossings over the platform location on daily probe trials (B). Performance during reversal learning was comparable between genotypes as measured by path to escape (C) and the number of crossings over the old and new platform locations during probe trials (D). (E) Fmr1 KO rats swim faster than WT littermates over all days tested.
Figure 4. Fmr1 KO rats have normal spatial reference memory acquisition and reversal learning. (A) Fmr1 KO rats learn the hidden-platform version of the water maze similarly to WT littermates as measured by a decrease over days in the path taken to escape (A) and the number of crossings over the platform location on daily probe trials (B). Performance during reversal learning was comparable between genotypes as measured by path to escape (C) and the number of crossings over the old and new platform locations during probe trials (D). (E) Fmr1 KO rats swim faster than WT littermates over all days tested.CC BY-NC · PubMed Central
Figure 5. One-trial spatial learning is intact in Fmr1 KO rats. (A) A schematic of the DMP version of the water maze task. (B) Fmr1 KO rats learn the DMP task similarly to WT littermates as measured by a decrease in the path length taken to escape over trials within a day. Introducing a variable time delay between the first and second trials of the day does not affect performance of Fmr1 KO rats compared with WT as measured by path length to escape (C), savings (D), time spent searching in the target zone on probe trials (E) or perseveration around the location of the target on the previous day on probe trials (F).
Figure 5. One-trial spatial learning is intact in Fmr1 KO rats. (A) A schematic of the DMP version of the water maze task. (B) Fmr1 KO rats learn the DMP task similarly to WT littermates as measured by a decrease in the path length taken to escape over trials within a day. Introducing a variable time delay between the first and second trials of the day does not affect performance of Fmr1 KO rats compared with WT as measured by path length to escape (C), savings (D), time spent searching in the target zone on probe trials (E) or perseveration around the location of the target on the previous day on probe trials (F).CC BY-NC · PubMed Central
Figure 6. Loss of FMRP results in impaired performance on a hippocampus-dependent novelty preference task. (A) A schematic of the spontaneous exploration tasks for novelty preference. (B) WT rats exhibit memory for all four tasks as measured by above chance performance. (C) In contrast, Fmr1 KO rats do not perform above chance levels in an OPC task that requires the ability to form associations between objects, their locations and the context, but do exhibit memory for the individual components as measured by above chance performance in object recognition, object-place and object-context tasks.
Figure 6. Loss of FMRP results in impaired performance on a hippocampus-dependent novelty preference task. (A) A schematic of the spontaneous exploration tasks for novelty preference. (B) WT rats exhibit memory for all four tasks as measured by above chance performance. (C) In contrast, Fmr1 KO rats do not perform above chance levels in an OPC task that requires the ability to form associations between objects, their locations and the context, but do exhibit memory for the individual components as measured by above chance performance in object recognition, object-place and object-context tasks.CC BY-NC · PubMed Central

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Metadata

Authors
Till, S. M., Asiminas, A., Jackson, A. D., Katsanevaki, D., Barnes, S. A., Osterweil, E. K., Bear, M. F., Chattarji, S., Wood, E. R., Wyllie, D. J. A., & Kind, P. C.
Affiliations
  • University of Edinburgh (GB)
  • Institute for Stem Cell Biology and Regenerative Medicine (IN)
  • Howard Hughes Medical Institute (US)
  • Tata Institute of Fundamental Research (IN)
Corresponding author
Kind, Peter C.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2015-08-04
Volume
24
Issue
21
Pages
5977-5984
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddv299
PMC
PMC4599667
OpenAlex
W1893201598
Cited by
109
References
28
Citations by year
2026: 6 · 2025: 8 · 2024: 7 · 2023: 3 · 2022: 16 · 2021: 9 · 2020: 16 · 2019: 9 · 2018: 13 · 2017: 11 · 2016: 10 · 2015: 1
FWCI
8.02
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • Oxford University Press eBooks
Funders
  • Wellcome Trust (104116, 104116/Z/14/Z)
  • Research Councils UK
  • University of Edinburgh
  • Medical Research Council (MR/K014137/1, MR/M006336/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
fragile X syndrome, FMRP, hippocampus, CA1 pyramidal neurons, dendritic spines, protein synthesis, synaptic plasticity, associative recognition memory, episodic-like memory, spatial memory, cross-species conservation, transgenic rats
MeSH terms
Animals, Disease Models, Animal, Female, Fragile X Syndrome, Hippocampus, Male, Memory Disorders, Neuronal Plasticity, Species Specificity, Rats, Sprague-Dawley, Pyramidal Cells, Maze Learning, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Gene Knockout Techniques

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