Neural repolarization in schizophrenia

Although evidence clearly indicates that genetic factors contribute to schizophrenia, it has been difficult to link specific gene variants with disease-related alterations in cognition, physiology, brain structure, or molecular signaling. In this paper the authors performed a meta-analysis of 5 independent clinical association data sets and identified the gene KCNH2, an ether-a-go-go (ERG) family potassium channel, as a potential schizophrenia susceptibility gene.  Four SNPs were significantly associated and mapped to intron 2 of the gene. Analysis of transcripts led to identification of a primate-specific isoform (3.1) whose expression was increased in the hippocampus of individuals with schizophrenia and in healthy control carriers of risk-associated SNPs. These healthy carriers also showed lower IQ scores, reduced speed of cognition, decreased hippocampal volumes, and inefficient memory and executive function proportional to allelic load in the hippocampus and dorsolateral prefrontal cortex by fMRI. In vitro, KCNH-3.1 channels showed faster inactivation kinetics compared with the KCNH2-1A isoform. Over-expression of KCNH2-3.1 channels in rat primary cortical neurons induced a high frequency, non-adapting firing pattern. These results suggest that disease risk variants in KCNH2 increase expression of the KCNH2-3.1, which leads to increased neuronal excitability in the prefrontal cortex and hippocampus, disturbing information processing and predisposing to psychosis. The results remain to be replicated and the molecular mechanisms by which disease-associated SNP variants alter RNA splicing remain to be determined. Nevertheless these results suggest that variants in KCNH2 contribute to risk of schizophrenia and that the KCNH2 channel may be a new target for antipsychotic drugs (Nat Med 2009;15:509-518).