KCNJ6 variants modulate reward‐related brain processes and impact executive functions in attention‐deficit/hyperactivity disorder

Abstract

KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopaminerelated brain processes in ADHD risk. K E Y W O R D S ADHD, dopamine, executive functions, KCNJ6, reward

A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

“…This is underlined by an association of rs2199430 with the personality trait of agreeableness and by allele-specific alterations of neural response patterns during a working memory task in our aADHD cohort. Hence, this study joins the growing line of evidence that the investigation of disease-related intermediate phenotypes is practical for disentangling the contribution of pleiotropic variants to genetically complex neuropsychiatric diseases [ 26 , 40 , 45 , 46 ].…”

“…Both tasks revealed alterations in ADHD vs. control groups in previous studies, with inattentive symptoms negatively influencing n-back performance and high impulsivity disturbing the ability to suppress prepared motor responses, leading to commission errors during CPTs (Go-response on NoGo trials) by hasty acting [ 36 ]. Altered event-related potentials (ERPs) during n-back tasks and CPTs measured by EEG have been described as pathophysiological correlates of ADHD both generally [ 37 , 38 ] and in conjunction with copy number and single nucleotide variation of risk genes in ADHD [ 39 , 40 ]. Therefore, we analyzed the association of rs2199430 genotype with task performance and ERPs during an n-back and Go-NoGo (CPT) trial.…”

“…ADHD patients were either medication-naive or had to pause psychostimulant treatment at least 3 days prior to testing. As in our previous publications [ 39 , 40 ], the number of omission and commission errors, reaction times to target/Go stimuli, and the standard deviation of reaction times were considered as behavioral data both for the n-back and the CPT. Electrophysiologically, amplitudes of the N200 (at fronto-central electrode positions: F3, Fz, F4, C3, Cz, C4) and P300 (at centro-parietal positions: C3, Cz, C4, P3, Pz, P4) were regarded as indicators of inhibition and (the reallocation of) attention, respectively, for the n-back task.…”

“…For the CPT, a topographical analysis was conducted focusing on a posterior-anterior shift in the brain electrical field of the P300 from Go to NoGo trials, i.e., the NoGo anteriorization (NGA; see [ 41 ]). For more details on the electrophysiological measurements and analyses, please refer to our previous publications [ 39 , 40 ].…”

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

“…Several transcripts that are key regulators of synaptic signaling were present in each of the modules that were significantly enriched for transcripts that were more rhythmic in the NAc of OUD subjects. These transcripts included: GRIN3A 48,49 , SLC6A7 50 , KCNJ6 51,52 , GABRQ 53 , and HPCAL1 54 (brown module); SEMA5B 55 and SHISA6 56 (pink module); and PCP4 57 and PPP1R1B (DARPP-32) 58 (red module). Pathway enrichment analyses of transcripts comprising the networks in brown, pink, and red modules further supported the connection between rhythmic transcripts in OUD and synaptic function in the NAc, including neurotransmitter receptors and postsynaptic signal transmission, trans-synaptic signaling, positive regulation of excitatory postsynaptic potential, and pathways related to extracellular matrices (ECM) and brain morphology (e.g., ECM glycoproteins, cell-cell adhesion molecules, and axon development) (Fig.…”