Decreased Brain Serotonin Transporter Binding in ASD [Nakamura et al., 2010]
Serotonin has been implicated in ASD since the initial report of increased serotonin in the blood of children with ASD in 1961 [Schain & Freedman, 1961]. After decades of investigation, the mechanism of the elevation in blood serotonin is not fully understood, although either reduced serotonin 5-HT2 binding or increased serotonin transporter function were found in hyperserotonemic subjects in one study [Cook et al., 1993]. It is important to recognize that the peripheral serotonin increase applies only to a minority of subjects with ASD. Because of challenges in measuring central serotonin function in ASD, there have been few previous studies of serotonin in the brains of individuals with ASD. To date, in vivo study of serotonin in brain has been limited to studies in which radioactively tagged molecules (radioligands) that bind to serotonin proteins (serotonin receptors or transporters) are administered intravenously and taken into the brain where they bind to 5-HT receptors (e.g. 5-HT2) or the 5-HT transporter. SPECT or PET methods are then used to measure binding of the radioligands to the brain serotonin-related proteins.
The authors used the compound [11C]-trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methyltrio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) as a radioligand to bind to serotonin transporter molecules. The radioligand 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C] WIN-35,428) was used to study dopamine transporter binding. An increase in WIN-35,428 binding was found in the orbital frontal cortex. However, since it was P 0.02 voxel-corrected (in the region), but not a multiple region-corrected finding, it may have occurred by chance. Therefore, the reported inverse correlation with serotonin transporter binding in the ASD subjects in this region may have occurred by chance as well. Therefore, the remainder of the review will focus on serotonin transporter binding.
Compared to 20 age- and IQ-matched control men, the 20 adult men (age range 18–26 years; IQ mean 99.3 and standard deviation 18.1) with ASD had reduced serotonin transporter binding throughout the brain. The authors spent considerable time in the manuscript discussing regional differences both in magnitude of the reduction and in correlation with ASD symptoms. However, given the global nature of the reduction and the effects of imprecision of measurement of regions of interest with PET, the regional differences in correlations with symptoms were less convincing.
It would have been useful to have measured blood serotonin and related measures (e.g. platelet serotonin transporter binding and function). It would also have been useful to have genotyped controls and individuals with ASD both for common variants regulating gene expression and rare amino acid variants altering protein function of the serotonin transporter. Without those measures, the paradox of a minority of subjects with increased 5-HT transporter function peripherally cannot be reconciled with the current study's finding of reduced central 5-HT transporter function of the whole group. One possibility is that a minority of subjects with ASD have increased serotonin transporter function but that the larger group may have a reduction in serotonin transporter function, but that will require further investigation.
This focused study provides information about the overall finding of reduced serotonin transporter binding in ASD in a group of subjects that as a whole had average IQ scores. Further study will be necessary to understand the relationship of this overall finding to specific aspects of phenotype in ASD.