Molecular correlates of topiramate and GRIK1 rs2832407 genotype in pluripotent stem cell-derived neural cultures

There is growing evidence that the anticonvulsant topiramate is efficacious in reducing alcohol consumption. Further, an intronic single nucleotide polymorphism (rs2832407, C ➔ A) in the GRIK1 gene, which encodes the GluK1 subunit of the excitatory kainate receptor, predicted topiramate’s effectiveness in reducing heavy drinking in a clinical trial. In the current study, we differentiated a total of 22 induced pluripotent stem cell (iPSCs) lines characterized by GRIK1 rs2832407 genotype (10 A/A and 12 C/C) into forebrain-lineage neural cultures to explore molecular correlates of GRIK1 genotype that may relate to topiramate’s ability to reduce drinking. Our differentiation protocol yielded mixed neural cultures enriched for glutamatergic neurons. Characterization of the GRIK1 locus revealed no effect of rs2832407 genotype on GRIK1 isoform mRNA expression, however a significant difference was observed on GRIK1 antisense-2, with higher expression in C/C neural cultures. Differential effects of acute exposure to 5 μM topiramate were observed on the frequency of spontaneous synaptic activity in A/A vs. C/C neurons, with a smaller reduction in excitatory event frequency and a greater reduction in inhibitory event frequency observed in C/C donor neurons. This work highlights the use of iPSC technologies to study pharmacogenetic treatment effects in psychiatric disorders and furthers our understanding of the molecular effects of topiramate exposure in human neural cells.