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

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).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.These changes may be responsible for cognitive deficits and seizure disorder in people with autism.Autism and fragile X syndrome (FXS) are two disorders that share several commonalities, including reduced cerebellar volume, altered dendritic spine morphology [1-4], presence of seizures, mental retardation and social anxiety [2-5], as well as other behavioral abnormalities [5,6]. People with both FXS and autism have been shown to have lower IQ scores [7], lower adaptive skills [7], lower expressive language skills [8] and greater autonomic dysfunction and hyperarousal [9] than people with FXS alone. The rate of FXS in people with autism varies from 2% to 8% [10,11]. The prevalence of autism in people with FXS has been estimated to be anywhere from 25% to 47% [5,12,13].All diagnoses of FXS require loss of function mutation of the fragile X mental retardation 1 (FMR1) gene [14]. The product of the FMR1 gene, fragile X mental retardation protein (FMRP), has roles in multiple intranuclear and posttranscriptional events [15,16] and has been shown to bind to up to 4% of the mRNA expressed in the brain [17]. FMRP is thought to be involved in multiple developmental events