Progressive spatial processing deficits in a mouse model of the fragile X premutation

Abstract

Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that is the result of a CGG trinucleotide repeat expansion in the range of 55-200 in the 5' UTR of the FMR1 gene. To better understand the progression of this disorder, a knock-in (CGG KI) mouse was developed by substituting the mouse CGG8 trinucleotide repeat with an expanded CGG98 repeat from human origin. It has been shown that this mouse shows deficits on the water maze at 52 weeks of age. In the present study, this CGG KI mouse model of FXTAS was tested on behavioral tasks that emphasize spatial information processing. The results demonstrate that at 12 and 24 weeks of age, CGG KI mice were unable to detect a change in the distance between two objects (metric task), but showed intact detection of a transposition of the objects (topological task). At 48 weeks of age, CGG KI mice were unable to detect either change in object location. These data indicate that hippocampal-dependent impairments in spatial processing may occur prior to parietal cortex-dependent impairments in FXTAS.

Figure 1

A. Diagram and timeline for the metric spatial processing task. B. Diagram and timeline for the topological spatial processing task. Notice that the habituation sessions are identical between the tasks, with only the object manipulation differing between the habituation and test sessions.

Figure 2. Habituation of Object Exploration

A. Plots showing habituation of object exploration for the metric spatial processing task. At each age the CGG KI group showed a decrease in exploration during the test compared to the last 5 min of the habituation session, whereas the wildtype group showed a marked increase in exploration during the test. B. Habituation of object exploration for the topological spatial processing task. At 12 weeks and 24 weeks both group showed similar increases in object exploration during the test session. However, at 48 weeks of age the CGG KI group showed similar levels of re-exploration during the test session compared to the last 5 min of the habituation session, while the wildtype group showed a large increase in exploration. The data for MIN 11-15 and the 5 min TEST sessions were used to generate the Mean Ratio Scores reported in figures 3A and 3B.

Figure 3. Metric and Topological Spatial Processing

A. Mean Ratio Scores for wildtype and CGG KI mice at different ages for the metric task B. Mean Ratio Scores for the topological task. (12 weeks of age CGG KI n=8, wildtype=8; 24 weeks of age CGG KI n=10, wildtype=8; 48 weeks of age CGG KI n=8, wildtype=10). * p<0,05, ** p<0.01.

Figure 4. Intranuclear Inclusions in 12, 24, and 48 Week Old Animals Stained for Ubiquitin and Countertained with Neutral Red

A. 12 Week old animals have inclusions in the dentate gyrus granule cells, but (B) not in the parietal cortex C. 24 Week old animals have inclusions in the dentate gyrus granule cells, but (D) not in the parietal cortex. cortex. E. 48 week old animals have inclusions in the granule cells in the dentate gyrus, and, (F) in the parietal cortex. Arrowheads point to neurons with ubituitin stained intranuclear inclusions. Insets show a representative cell enlarged to show inclusions. Scale bar in D is 50 μM and applies to all plates, but not to inserts.