Differential serotonin transporter (5-HTT) and 5-HT 2 receptor density in limbic and neocortical areas of adults and children with autism spectrum disorders: implications for selective serotonin reuptake inhibitor efficacy

J Neurochem. 2019 Dec;151(5):642-655. doi: 10.1111/jnc.14832. Epub 2019 Oct 27.

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 [3 H]-citalopram (5-HTT), [3 H]-ketanserin (5-HT2 ), and [3 H]-8-OH-DPAT (5-HT1A ). A Welch's t-test was utilized to compare receptor densities (Bmax ), 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 Bmax 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 (KD ) across all regions and ligands examined.

Keywords: 5-HT1A); anterior cingulate cortex; autism; selective serotonin reuptake inhibitors (SSRIs); serotonin receptors (5-HT2; serotonin transporter (5-HTT).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autism Spectrum Disorder / metabolism*
  • Brain / metabolism*
  • Child
  • Female
  • Humans
  • Male
  • Receptors, Serotonin, 5-HT2 / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Uptake Inhibitors / pharmacokinetics*
  • Young Adult

Substances

  • Receptors, Serotonin, 5-HT2
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors