Social-emotional and social-communicative behaviors are core features of autism and two of the key affected substrates are the cingulate cortices and fusiform gyrus. There is neuropathology within cortical lamina as well as changes in GABA-A receptors and associated benzodiazepine binding sites in both the anterior (ACC) and posterior (PCC) cingulate areas and in the fusiform (FG), a key area for the perception of facial expressions, shown to be altered in adult individuals with autism. Peripheral serotonin (5-HT) changes have been well characterized including increased blood 5-HT levels (hyperserotonemia) but alterations in central 5-HT have been mainly limited to imaging studies in high functioning ASD. These include altered 5-HT synthesis and reduced 5-HT2A receptors. A detailed quantitative histological laminar analysis of 5-HT transporters (5-HTT) and major receptor subtypes (5-HT1A;5-HT2A) within specific cortical areas is virtually lacking in the literature. Pharmacological treatment in children and adults with autism has focused on selective serotonin reuptake inhibitors (SSRIs) that have yielded mixed results as well as detrimental effects and has been brought under question as to their effectiveness. The SSRIs are primarily directed toward 5-HTT without having prior knowledge of central changes in the density, number, distribution or affinity of the serotonin transporters or receptors within cortica areas. The central objective of this proposal is to determine the number (Bmax) and binding affinity (Kd) of the 5-HTT, 5-HT1A and/or 5-HT2A receptors in the ACC, PCC and FG in adult individuals with autism compared to age- and postmortem-interval matched controls, and their relationship with social-communication behavior. Data will directly demonstrate whether the transporters or receptor type(s) are impacted in autism and suggest which biomarker(s) should be considered for targeted pharmacotherapeutic treatment to improve function. Preliminary evidence from single concentration ligand binding studies have led to our hypothesis that it is the 5-HT1A and 5-HT2A receptors that are strongly affected in the ACC, PCC and FG and not the 5-HTT thus implicating them as novel and redirected targets for potential clinical studies. To definitively determine changes in 5-HTT, 5-HT1A and/or 5-HT2A receptors, multiple-concentration (saturation) ligand binding studies are proposed in Specific Aim 1 that will utilize seven concentrations of ligand to produce binding curves and data that will quantitatively determine the number (Bmax) and binding affinity (Kd) for each transporter or receptor type.
In Specific Aim 2, we will evaluate the relationship of social-communication symptom severity to 5-HTT and receptor number in superficial and deep layers of the ACC, PCC and FG. We will explore the hypothesis that decreased 5-HT receptor subtypes, but not 5-HTT, will be associated with increased social-communication symptom severity in individuals with autism measured via each subject's ADI-R diagnostic algorithm. This novel approach will translate across neuropathology/neurochemistry to the clinical behavioral domain thus suggesting a potential alternative approach to treatment of affected individuals.
There is a controversy as to whether selective serotonin reuptake inhibitors (SSRIs) are effective as therapeutic agents in individuals with autism and recent reports indicate that there may even be adverse effects. This project focuses on both the serotonin transporter (5-HTT) and two major serotonin (5-HT) receptor subtypes, 5-HT1A and 5-HT2A in the cingulate cortices and fusiform gyrus, areas that are important in social-emotional behavior and interpretation of facial expressions respectively. Quantitative data from this study may help guide pharmacotherapies and will also determine whether there is a relationship between specific serotonin receptor subtypes and social-communication deficits in individuals with ASD.
|Subramanian, Krishna; Brandenburg, Cheryl; Orsati, Fernanda et al. (2017) Basal ganglia and autism - a translational perspective. Autism Res 10:1751-1775|