Glutamate receptor genetic variants affected peripheral glutamatergic transmission and treatment induced improvement of Indian ADHD probands

Abstract

Attention deficit hyperactivity disorder (ADHD), a childhood-onset neurobehavioral disorder, often perturbs scholastic achievement and peer-relationship. The pivotal role of glutamate (Glu) in learning and memory indicated an influence of Glu in ADHD, leading to the exploration of Glu in different brain regions of ADHD subjects. We for the first time analyzed GluR genetic variations, Glu levels, as well as expression of Glu receptors (GluR) in the peripheral blood of eastern Indian ADHD probands to find out the relevance of Glu in ADHD prognosis. After obtaining informed written consent for participation, peripheral blood was collected for analyzing the genetic variants, Glu level, and expression of target genes. Since ADHD probands are often treated with methylphenidate or atomoxetine for providing symptomatic remediation, we have also tested post-therapeutic improvement in the ADHD trait scores in the presence of different GluR genotypes. Two variants, GRM7 rs3749380 “T” and GRIA1 rs2195450 “C”, exhibited associations with ADHD (P ≤ 0.05). A few GluR genetic variants showed significant association with higher trait severity, low IQ, lower plasma Glu level, down-regulated GluR mRNA expression, and poor response to medications. This indicates that down-regulated glutamatergic system may have an effect on ADHD etiology and treatment efficacy warranting further in-depth investigation.