SLC2A3 copy number variants in ADHD – from cellular to clinical correlates

Introduction A duplication of the SLC2A3 gene is associated with adult ADHD and leads to alterations of event-related potentials (ERPs) in executive tasks. SLC2A3 is encoding the neuronal glucose transporter GLUT3 which is crucial for neuronal energy homeostasis. We hypothesize that copy number variants (CNVs) of the SLC2A3 gene lead to a gene-dosage effect with consequences for cellular glucose uptake and promote changes on various endophenotypic levels in ADHD.

Methods SLC2A3 expression levels and glucose uptake were assayed in peripheral cell models and iPSC-derived neuronal cell lines. Neuropsychological correlates of SLC2A3 CN were assessed by linear regression analysis of questionnaire data. To address possible alterations on the neural systems level, fMRI (ERPs to food cues) was performed.

Results Despite increased mRNA expression, the SLC2A3 duplication did not lead to changes in GLUT3 protein levels and no effect on cellular glucose uptake was found. However, there is an inverse correlation of SLC2A3 CN with ADHD symptoms in the female subgroup. Furthermore, the SLC2A3 duplication was associated with an altered multivariate neural response pattern towards high-caloric food stimuli.

Conclusion With iPSCs we have a powerful tool at hand to investigate the consequences of SLC2A3 CNVs beyond gene expression levels in the future. This will be helpful to disentangle molecular biologic consequences of SLC2A3 CNVs. SLC2A3 plays a role in the neural processing of food cues which might be well in line with the known problem of impulsive overeating in ADHD. Our neuropsychologic data, however, speak against a strict categorical association of SLC2A3 CNVs with ADHD.