Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation

Abstract

Background: The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive.

Methods: We completed functional magnetic resonance imaging targeting the amygdala with an emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years).

Results: Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to control subjects. Although both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than control subjects, which were associated with the reduced amygdala response.

Conclusions: Although prior studies have emphasized a toxic gain-of-function effect of elevated messenger RNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior.

Figure 1

Sample trials of the emotion matching task (33). Participants matched the bottom emotion to either the top left or top right emotion. For the control trials, participants matched the shapes.

Figure 2

Distributions of left and right amygdala volume (corrected for total cerebral volume) in premutation carriers and controls.

Figure 3

Whole brain within group analysis in the emotion > control condition for controls and premutation carriers. Significant clusters were thresholded on the voxel level at p < 0.01 after FDR correction. Both groups significantly activated the bilateral amygdala during this task. Bars at left represent degree of activation using the t-statistic.

Figure 4

Scatterplots showing the association between right (top) and left (bottom) amygdala activation (contrast value extracted from ROI analyses) and FMRP in premutation carriers.