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.

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

“…Naturally, research has focused on the molecular and biochemical changes that result from loss of FMRP and potential compensatory and therapeutic targets (Tamanini et al, 1996; Hagerman et al, 2010; Sharma et al, 2010; Bhattacharya et al, 2012). This is partly because of the impressive progress in understanding FXS, which began by identifying the cause (Pieretti et al, 1991), a CGG trinucleotide repeat expansion exceeding 200 repeats, leading to loss of FMRP and then modeling it by deletion of Fmr1 in mice (Bakker et al, 1994) and recently rats (Till et al, 2015). In vitro physiological investigation was then successful in characterizing and delineating synaptic dysfunctions that are associated with Fmr1 KO.…”

“…Cognitive discrimination deficits are prominent in Fmr1 knockout (KO) rodents that do not make FMRP, although learning and memory per se are relatively normal (Bakker et al, 1994; D’Hooge et al, 1997; Zhao et al, 2005; Brennan et al, 2006; Bhattacharya et al, 2012; Till et al, 2015). Indeed, loss of FMRP did not alter activity-dependent synaptic plasticity in cultured neurons (Segal et al, 2003) but is associated with enhanced mGluR-stimulated hippocampal long-term depression (LTD) (Huber et al, 2002).…”

BDNF controls object recognition memory reconsolidation

“…We defined exploration as sniffing or touching the stimuli objects with the muzzle and/or forepaws. A discrimination index (DI = (Time exploring novel object À Time exploring familiar object)/Total object exploration time) was used as a measure of discrimination between familiar and novel objects (Aggleton, Albasser, Aggleton, Poirier, & Pearce, 2010;Aubele, Kaufman, Montalmant, & Kritzer, 2008;Langston & Wood, 2010;Cohen et al, 2008;Till et al, 2015). DI varies between À1 and +1.…”

Hyperactive locomotion in a Drosophila model is a functional readout for the synaptic abnormalities underlying fragile X syndrome

“…Homozygous deletion of FMR1 ( FMR1-KO ) in rodents produces a dendritic spine abnormality that resembles the phenotype seen in FXS patients (6, 7). Furthermore, FMR1-KO mice and rats exhibit cognitive and behavioral traits, some of which are consistent with those of the FXS patients, such as hyperactivity as well as learning and memory defects (8).…”