Metabotropic glutamate receptor genetic variants and peripheral receptor expression affects trait scores of autistic probands.

Glutamate (Glu) is important for memory and learning. Hence, Glu imbalance is speculated to affect autism spectrum disorder (ASD) pathophysiology. The action of Glu is mediated through receptors and we analyzed four metabotropic Glu receptors (mGluR/GRM) in Indo-Caucasoid families with ASD probands and controls. The trait scores of the ASD probands were assessed using the Childhood Autism Rating Scale2-ST. Peripheral blood was collected, genomic DNA isolated, and GRM5 rs905646, GRM6 rs762724 & rs2067011, and GRM7 rs3792452 were analyzed by PCR/RFLP or Taqman assay. Expression of mGluRs was measured in the peripheral blood by qPCR. Significantly higher frequencies of rs2067011 'A' allele/ AA' genotype were detected in the probands. rs905646 'A 'exhibited significantly higher parental transmission. Genetic variants showed independent as well as interactive effects in the probands. Receptor expression was down-regulated in the probands, especially in the presence of rs905646 'AA', rs762724 'TT', rs2067011 'GG', and rs3792452 'CC'. Trait scores were higher in the presence of rs762724 'T' and rs2067011 'G'. Therefore, in the presence of risk genetic variants, down-regulated mGluR expression may increase autistic trait scores. Since our investigation was confined to the peripheral system, in-depth exploration involving peripheral as well as central nervous systems may validate our observation.

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

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.

Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder.

BACKGROUND: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders. METHODS: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5' flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated. RESULTS: A significantly higher occurrence of rs1800955 "T/TT" was observed in the probands. ASD traits were affected by rs1800955 "T" and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 "6R" and rs27072 "CC" and DRD4 rs4646984 higher repeat allele and rs1800955 "T". CONCLUSION: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis.

Kainate receptor subunit 1 (GRIK1) risk variants and GRIK1 deficiency were detected in the Indian ADHD probands.

Executive dysfunctions caused by structural and functional abnormalities of the prefrontal cortex were reported in patients with Attention deficit hyperactivity disorder (ADHD). Owing to a higher expression of the glutamate ionotropic receptor kainate type subunit 1 (GluK1), encoded by the GRIK1 gene, in brain regions responsible for learning and memory, we hypothesized that GRIK1 might have a role in ADHD. GRIK1 variants rs363504 and rs363538, affecting the receptor function, were analyzed by case-control and family-based methods to identify the association with ADHD. The impact of these variants on ADHD-associated traits and pharmacological intervention were also analyzed. GRIK1 expression was quantified in the peripheral blood. The probands and their fathers had a higher frequency of rs363504 'CC' and rs363538 'CA' genotypes. Family-based investigation revealed maternal over transmission of rs363504 'C' and rs363538 'A' alleles to the probands. Quantitative trait analysis exhibited an association of rs363504 'TT' and rs363538 'AA' genotypes with higher hyperactivity scores of the probands. In the presence of rs363504 'TT' and rs363538 'CC' genotypes, MPH treatment improved hyperactivity and inattention, respectively. GRIK1 expression was significantly downregulated in the probands. We infer that GRIK1 affects ADHD etiology, warranting further in-depth investigation involving a larger cohort and more functional variants.

GABA Receptor SNPs and Elevated Plasma GABA Levels Affect the Severity of the Indian ASD Probands.

Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABAA-receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 "A," GABRG3 rs897173 "A," and GABRA5 rs140682 "T" showed significant association with ASD. Trait scores were influenced by rs1432007 "AA" and rs140682 "TT." GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands.