Department of Biotechnology
inStem (Institute for Stem Cell Science and Regenerative Medicine)

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

Publication Type

Research Support, Non-U.S. Gov't

Date of Publication

November 1, 2015

Journal

Human molecular genetics

Volume/Issue

24/21

ISSN

1460-2083

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.

Alternate Journal

Hum Mol Genet

PubMed ID

26243794

PubMed Central ID

PMC4599667

Authors

Sally M Till
Antonis Asiminas
Adam D Jackson
Danai Katsanevaki
Stephanie A Barnes
Emily K Osterweil
Mark F Bear
Sumantra Chattarji
Emma R Wood
David J A Wyllie
Peter C Kind

Keywords

Disease Models, Animal
Species Specificity
Maze Learning
Gene Knockout Techniques
Rats
Fragile X Mental Retardation Protein
Hippocampus
Rats, Sprague-Dawley
Animals
Memory Disorders
Neuronal Plasticity
Female
Fragile X Syndrome
Male
Pyramidal Cells