Abstract
Previous functional MRI (fMRI) studies have shown that fragile X mental retardation 1 (FMR1) fragile X premutation allele carriers (FXPCs) exhibit decreased hippocampal activation during a recall task and lower inferior frontal activation during a working memory task compared to matched controls. The molecular characteristics of FXPCs includes 55–200 CGG trinucleotide expansions, increased FMR1 mRNA levels, and decreased FMRP levels especially at higher repeat sizes. In the current study, we utilized MRI to examine differences in hippocampal volume and function during an encoding task in young male FXPCs. While no decreases in either hippocampal volume or hippocampal activity were observed during the encoding task in FXPCs, FMRP level (measured in blood) correlated with decreases in parahippocampal activation. In addition, activity in the right dorsolateral prefrontal cortex during correctly encoded trials correlated negatively with mRNA levels. These results, as well as the established biological effects associated with elevated mRNA levels and decreased FMRP levels on dendritic maturation and axonal growth, prompted us to explore functional connectivity between the hippocampus, prefrontal cortex, and parahippocampal gyrus using a psychophysiological interaction analysis. In FXPCs, the right hippocampus evinced significantly lower connectivity with right ventrolateral prefrontal cortex (VLPFC) and right parahippocampal gyrus. Furthermore, the weaker connectivity between the right hippocampus and VLPFC was associated with reduced FMRP in the FXPC group. These results suggest that while FXPCs show relatively typical brain response during encoding, faulty connectivity between frontal and hippocampal regions may have subsequent effects on recall and working memory.
Highlights
The weaker connectivity between the right hippocampus and ventrolateral prefrontal cortex (VLPFC) was associated with reduced fragile X mental retardation protein (FMRP) in the fragile X premutation carriers (FXPC) group.These results suggest that while FXPCs show relatively typical brain response during encoding, faulty connectivity between frontal and hippocampal regions may have subsequent effects on recall and working memory
The premutation expansion (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene is linked to mood and other psychological symptoms (Franke et al, 1998; Johnston et al, 2001; Cornish et al, 2005; Hessl et al, 2005, 2007, 2011; Roberts et al, 2009), executive dysfunction (Cornish et al, 2005; Kogan and Cornish, 2010), primary ovarian insufficiency (POI; AllinghamHawkins et al, 1999; Murray et al, 2000; Sullivan et al, 2005), and a late life neurodegenerative disorder characterized by intention tremor and gait ataxia, the fragile X-associated tremor ataxia syndrome (FXTAS; Hagerman et al, 2001; Jacquemont et al, 2003; Leehey, 2009; Garcia-Arocena and Hagerman, 2010)
FMRP was reduced by 23% in the FXPC group relative to controls (FXPCs: mean = 77.08, SD = 67.15; Controls: mean = 100.38, SD = 56.90); this difference did not reach statistical significance, possibly as a result of high variability within both groups
Summary
The premutation expansion (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene is linked to mood and other psychological symptoms (Franke et al, 1998; Johnston et al, 2001; Cornish et al, 2005; Hessl et al, 2005, 2007, 2011; Roberts et al, 2009), executive dysfunction (Cornish et al, 2005; Kogan and Cornish, 2010), primary ovarian insufficiency (POI; AllinghamHawkins et al, 1999; Murray et al, 2000; Sullivan et al, 2005), and a late life neurodegenerative disorder characterized by intention tremor and gait ataxia, the fragile X-associated tremor ataxia syndrome (FXTAS; Hagerman et al, 2001; Jacquemont et al, 2003; Leehey, 2009; Garcia-Arocena and Hagerman, 2010). The premutation allele results in increased FMR1 mRNA levels and in some cases, decreases in fragile X mental retardation protein (FMRP; Tassone et al, 2000b; Kenneson et al, 2001). FMRP plays an important role in dendritic maturation (Chen et al, 2010) and the formation of axons and myelin (Greco et al, 2002, 2006). Both increases in Frontiers in Human Neuroscience www.frontiersin.org
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