Differential serotonin transporter (5‐HTT) and 5‐HT₂ receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy

Abstract

As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14–19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5‐HT transporter (5‐HTT) as well as to 5‐HT2 and 1A receptors (5‐HT₂, 5‐HT1A) was quantified in superficial and deep layers of each region using the ligands [3H]‐citalopram (5‐HTT), [3H]‐ketanserin (5‐HT2), and [3H]‐8‐OH‐DPAT (5‐HT1A). A Welch’s t‐test was utilized to compare receptor densities (B max), revealing a statistically significant decrease in 5‐HTT within the ACC of the entire autism cohort. There was also a decrease in 5‐HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of B max values plotted against age, shows a significantly lower intercept for 5‐HTT in autism (p = 0.025). 5‐HT₂ density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5‐HTT within the ACC in individuals with autism, while decreases in 5‐HT₂ density are age‐dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (K D) across all regions and ligands examined.

Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry

“…This distributed input from cortical areas opens several avenues where alterations in cortical systems could lead to disrupted processing in the striatum in ASD. As one example, the dorsal anterior cingulate cortex is an area that heavily innervates the striatum (for a review see: Haber, 2016 ) and a recent postmortem study from our laboratory revealed differences in serotonin receptor subtype densities that were age-dependent and not evident in the other cortical brain areas examined (Brandenburg and Blatt, 2019 ). D1R modulates GABA release in the direct pathway whereas D2R modulates GABA release mainly to the GABAergic GPe (i.e., on striatopallidal neurons) in the indirect pathway (for a review see: Gerfen and Bolam, 2010 ).…”

Serotonin transporter availability in adults with autism—a positron emission tomography study

“…Supported by preclinical studies, a neurodevelopmental 5-HT hypothesis of ASD has been suggested [19,22]. But while multiple genetic studies have linked functional variants of the 5-HTT gene SLC6A4 to ASD [19], postmortem studies in ASD show conflicting results [23][24][25], and in vivo evidence supporting 5-HT involvement in ASD is limited.…”

Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

“…In adults, however, fluoxetine and fluvoxamine improved repetitive behaviors with large effect-sizes, yet based on single small ( n = 30–37) studies [ 65 , 66 ]. Apart from the limited data for adults, such differences might be explained by different study designs, participant characteristics and age-dependent variability in treatment response [ 67 , 68 ].…”