Abstract
BackgroundAutism is a neurodevelopmental disorder that is first manifested during early childhood. Postmortem experiments have identified significantly elevated expression of metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and prefrontal cortex of individuals with autism.MethodsIn the current study we employed the mGluR5 tracer [18F]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]-FPEB) to quantify mGluR5 binding in vivo in adults with autism vs. healthy controls using positron emission tomography (PET).ResultsWe identified significantly higher [18F]-FPEB binding potential in the postcentral gyrus and cerebellum of individuals with autism. There was a significant negative correlation between age and [18F]-FPEB binding potential in the cerebellum but not in the postcentral gyrus. In the precuneus, [18F]-FPEB binding potential correlated positively with the lethargy subscale score for the Aberrant Behavioral Checklist (ABC). In cerebellum, there were significant negative correlations between [18F]-FPEB binding potential and ABC total score, ABC hyperactivity subscale score, and the ABC inappropriate speech subscale score.ConclusionsThese novel findings demonstrate for the first time that mGluR5 binding is altered in critical brain areas of subjects with autism, suggesting abnormal glutamate signaling in these regions. Finally, the correlations between altered [18F]-FPEB binding potential in the cerebellum and precuneus suggest that some autistic symptoms may be influenced by abnormal glutamate signaling.
Highlights
Autism is a neurodevelopmental disorder that is first manifested during early childhood
We aimed to investigate if metabotropic glutamate receptor 5 (mGluR5) expression in vivo replicated the results obtained by postmortem experiments and whether these changes positively correlated with autism symptom severity
We identified significantly elevated [18F]-FPEB binding potential in cerebellum (p < 0.016) and postcentral gyrus (p < 0.036), indicating increased mGluR5 binding in these brain regions (Table 3, Fig. 1)
Summary
Autism is a neurodevelopmental disorder that is first manifested during early childhood. Reduced levels of the main inhibitory brain neurotransmitter, gamma-aminobutyric acid (GABA), have been observed in multiple brain regions of subjects with autism including the temporal lobe (auditory cortex), primary motor cortex, and postcentral gyrus (somatosensory cortex) [8,9,10]. In vitro binding assays employing [3H]-labeled 3-methoxy5-pyridin-2-ylethynylpyridine (MPEPy) in prefrontal cortex tissue homogenates from subjects with fragile X syndrome (FXS) vs controls found a marginally significant increase in mGluR5 density (p < 0.058) in subjects with FXS [14] These findings are important in light of proposed treatments for autism [15] as well as schizophrenia and affective disorders [16] via the modulation of mGluR5 activity. MGluR5 modulation may improve symptoms of psychiatric disorders including autism in patients who have not improved via currently available treatment modalities
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