Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation

Abstract

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG repeat lengths between 70 and 350 has been developed and used to characterize the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial information. To further characterize cognitive deficits in the fragile X premutation, temporal ordering in CGG knock-in (CGG KI) mice was evaluated. Female CGG KI mice were tested for their ability to remember the temporal order in which two objects were presented. The results demonstrate that at 48 weeks of age, female CGG KI mice with CGG repeat expansions between 150 and 200 CGG repeats performed more poorly on tests of temporal order than wildtype mice, whereas female CGG KI mice with between 80 and 100 CGG repeats performed similarly to wildtype mice. No mice had any difficulty in detecting the presence of a novel object. These data suggest female CGG KI mice show a CGG repeat length-sensitive deficit for temporal ordering.

Figure 1. Temporal Ordering for Visual Objects Paradigm

Mice are presented with two copies of object 1 for 5 min followed by a 3 min intersession interval. This is repeated for objects 2 and 3. After the presentation of all three objects, mice are given a preference test wherein object 1 and object 3 are presented to the mouse and they are allowed to explore. Preferential exploration of object 1 over object 3 reflects intact temporal ordering. Visual Object Novelty Detection Paradigm. The novelty detection for visual objects paradigm has identical sessions 1-3, but the test session consists of object 1 and a never before seen novel object 4. Preferential exploration of a novel object 4 over object 1 reflects intact memory of object 1 as well as intact novelty detection.

Figure 2. Temporal Ordering and Novelty Detection for Visual Objects in female CGG KI mice

Wildtype mice and CGG KI mice from the low CGG repeat group (70-100 CGG repeats) do not significantly differ, whereas the high CGG repeat group (150-200 CGG repeats) shows a significantly lower ratio value than the other two groups (plotted are means +/- SEM; * p > .01; **p < .001). There were no differences for novel object detection.