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

Abstract

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.

Cocaine-Induced Gene Regulation in D1 and D2 Neuronal Ensembles of the Nucleus Accumbens Revealed by Single-Cell RNA Sequencing

“…Nrp2 is induced by repeated cocaine exposure and involved in axon guidance and synaptic transmission, potentially affecting neural circuit remodeling during withdrawal 74,75 . Another prominent marker regulated by cocaine is Grik1 42,76,77 , which encodes the glutamate receptor kainate-1 that participates in excitatory neurotransmission and is a target of topiramate, a medication used to reduce alcohol cravings. Relatedly, following chronic ethanol consumption, the PKA inhibitor, encoded by Pkib , has been found to be upregulated in the NAc 78 .…”

GRIK1 promotes glioblastoma malignancy and is a novel prognostic factor of poor prognosis

“…Yet, the molecular mechanisms of GBM invasive growth remain largely unknown. In brain regions responsible for learning and memory, GRIK1 is encoded by the GRIK1 gene [17], which is located on chromosome 21q21.1-22.1 [16]. In previous studies, the relationship between GRIK1 and disease has been studied in multiple fields [22,23,[27][28][29]31].…”

“…With similarity in between nucleotide and amino acid sequences, at least six gene families have been identified as encoding ionotropic glutamate receptors, and there are also three families of NMDA receptors, two families of KA receptors, and one family of AMPA receptors [ 16 ]. Brain areas involved in learning and memory contain GluK1, a subunit of the glutamate ionotropic receptor kainate type gene (GRIK1) [ 17 ], and the gene’s precise location is 21q21.1-22.1 [ 16 ]. These ligand-gated ion channels are crucial for healthy brain function and play a significant role in various neurological and behavioral disorders [ 18 ].…”