Elsevier

Biological Psychiatry

Volume 70, Issue 9, 1 November 2011, Pages 859-865
Biological Psychiatry

Archival Report
Decreased Fragile X Mental Retardation Protein Expression Underlies Amygdala Dysfunction in Carriers of the Fragile X Premutation

https://doi.org/10.1016/j.biopsych.2011.05.033Get rights and content

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.

Section snippets

Participants

Participants included 23 men with the FMR1 premutation (mean age 32.9 years) and 25 matched control subjects (mean age 30.1 years). FMR1 DNA testing was used to confirm allele status for all participants. None of the participants with the premutation were mosaic for either repeat size or methylation—all had between 55 and 200 CGG repeats with no methylation. The control group was matched for age, IQ, level of education, handedness, psychoactive medication use, and ethnicity. Group demographic

Results

Participant FMR1 genetic, demographic, and clinical descriptive statistics are shown in Table 1. The FMRP distribution was positively skewed and therefore log-transformed to achieve normality. Fragile X mental retardation protein was reduced by 12% in the premutation group relative to control subjects, t(38) = 2.19, p < .034. Premutation carriers had significantly higher ADOS total scores than control subjects, with mean level (5.87) somewhat below the autism spectrum cutoff (7). Two control

Discussion

The results of this study demonstrate that relative to control subjects, men with an FMR1 premutation allele had smaller amygdala volumes and reduced amygdala activation during an emotion-matching task. In contrast to our prior study (18), in this investigation, we were able to determine that aberrant amygdala function was more strongly associated with reduced FMRP (the cause of FXS) than abnormal elevation of FMR1 mRNA (the hypothesized toxic mRNA gain-of-function model underlying FXTAS). To

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