Dysregulation of fragile × mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study

Abstract

Background: Fragile × syndrome is caused by loss of function of the fragile × mental retardation 1 (FMR1) gene and shares multiple phenotypes with autism. We have previously found reduced expression of the protein product of FMR1 (FMRP) in vermis of adults with autism.

Methods: In the current study, we have investigated levels of FMRP in the superior frontal cortex of people with autism and matched controls using Western blot analysis. Because FMRP regulates the translation of multiple genes, we also measured protein levels for downstream molecules metabotropic glutamate receptor 5 (mGluR5) and γ-aminobutyric acid (GABA) A receptor β3 (GABRβ3), as well as glial fibrillary acidic protein (GFAP).

Results: We observed significantly reduced levels of protein for FMRP in adults with autism, significantly increased levels of protein for mGluR5 in children with autism and significantly increased levels of GFAP in adults and children with autism. We found no change in expression of GABRβ3. Our results for FMRP, mGluR5 and GFAP confirm our previous work in the cerebellar vermis of people with autism.

Conclusion: These changes may be responsible for cognitive deficits and seizure disorder in people with autism.

Figure 1

Expression of FMRP in superior frontal cortex of people with autism and matched controls.(A) Representative samples of fragile X mental retardation protein (FMRP) from controls (C) and people with autism (A). (B) Mean FMRP/neuron-specific enolase (NSE) ratios for people with autism (filled histogram bars) and controls are shown for Brodmann's area 9 (BA9). (C) Mean FMRP/β-actin ratios for people with autism (filled histogram bars) and controls are shown for BA9. Error bars express standard error of the mean. **P < 0.05.

Figure 2

Expression of mGluR5 in superior frontal cortex of people with autism and matched controls.(A) Representative samples of metabotropic glutamate receptor 5 (mGluR5) from controls (C) and people with autism (A). (B) Mean mGluR5 dimer and monomer/neuron-specific enolase (NSE) ratios for people with autism (filled histogram bars) and controls are shown for Brodmann's area 9 (BA9). (C) Mean mGluR5/β-actin ratios for people with autism (filled histogram bars) and controls are shown for BA9. Error bars express standard error of the mean. **P < 0.05.

Figure 3

(A) Representative samples of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and β-actin from controls (C) and people with autism (A). (B) Mean GFAP/β-actin ratios for people with autism (filled histogram bars) and controls are shown for Brodmann's area 9 (BA9). Error bars express standard error of the mean. **P < 0.05.

Figure 4

Expression of GABRβ3 in superior frontal cortex of people with autism and matched controls. (A) Representative samples of γ-aminobutyric acid (GABA) A receptor β3 (GABRβ3) from controls (C) and people with autism (A). (B) Mean GABRβ3/neuron-specific enolase (NSE) ratios for people with autism (filled histogram bars) and controls are shown for Brodmann's area 9 (BA9). (C) Mean GABRβ3/β-actin ratios for people with autism (filled histogram bars) and controls are shown for BA9. Error bars express standard error of the mean.