James Brasic1, Ayon Nandi2, David Russell4, Danna Jennings5, Olivier Barret6, Keith Slifer7, Thomas Sedlak3, John Seibyl4, Elizabeth Berry-Kravis8, Dean Wong9, Dejan Budimirovic7
1Psychiatry, New York University Grossman School of Medicine, 2Radiology and Radiological Science, 3Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 4Institute for Neurodegenerative Disorders, 5Denali Therapeutics, 6Molecular Imaging Research Center, 7Kennedy Krieger Institute, 8Rush University Medical Center, 9Washington University in St Louis
Objective:
To identify abnormalities in glutamatergic neurotransmission in autism spectrum disorder (ASD)
Background:
Based on animal and autopsy studies we hypothesized that metabotropic glutamate receptor subtype 5 (mGluR5) is increased in the brains of people with ASD.
Design/Methods:
Positron emission tomography (PET) was performed on participants of both sexes with idiopathic autism spectrum disorder (IASD) (N=7, age 19.71 + 2.06) and typical development (TD) (N=19, age 34.89 + 14.57) and men with fragile X syndrome (FXS) (N=10, age 29.7 + 10.39) after the intravenous bolus injection of 185 MBq (5 mCi) 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB). [18F]FPEB uptake was represented as nondisplaceable binding potentials (BPND) in cortical [occipital cortex (Oc), parietal cortex (Pc), posterior cingulate cortex (pCg), and temporal cortex (Tc)] and subcortical regions [caudate nucleus (CN), putamen (Pu), and thalamus (Th)].
Results:
Box and dot plots of descriptive BPND statistics demonstrated group differences across the regions. To confirm the effects of group status (IASD versus TD versus FXS), analysis of variance (ANOVA) was performed with main factors (group and region) and covariates (age and sex). To confirm the significant effect of group on mGluR5 uptake demonstrated by ANOVA, Tukey's Honest Standard Differences was performed for pairwise comparisons. In contrast to participants with TD, mGluR5 expressions was increased in the cortical regions of participants with IASD and reduced in all regions of men with FXS.
Conclusions:
mGluR5 expression was reduced in all FXS brain regions in contrast to IASD and TD. In men with FXS reduced mGluR5 expression in (A) cortical regions may suggest the pathophysiology for the intellectual disability and (B) limbic regions may suggest the pathophysiology for the neurobehavioral symptoms.
mGluR5 expression was increased in cortical regions of the participants with IASD in contrast to those with TD and FXS.
These findings support the hypothesis that mGluR5 expression plays a role in the pathogenesis of IASD.