CRISPR activation (CRISPRa) fuses a transcription activator domain to a “dead” Cas9 (lacking endonuclease activity), which is targeted to a selected promoter with a guide RNA and upregulates gene expression. 61 CRISPRa has been successfully implemented to investigate multiple eQTL gene variants associated with schizophrenia, resolving pre‐ and postsynaptic neuronal deficits together with genotype‐dependent gene expression. 62 By utilizing endogenous regulatory mechanisms, CRISPRa is different from ectopic overexpression because of potential effects of UTRs on protein localization and trafficking. This is particularly pertinent for KCNJ6 which has a long (19 kb) 3′UTR. Using CRISPRa, it will be possible to determine more precisely the effects of increased GIRK2 expression on neuronal function and the neuronal response to chronic ethanol exposure.
