Potassium Channel Linked to Schizophrenia

Areas in the prefrontal cortex (right) and hippocampus (left) where activity differed in healthy control subjects during thinking tasks, depending on whether they had the risk version of the KCNH2 potassium channel gene.NIMH

Scientists have connected a gene that regulates the flow of potassium into and out of cells with schizophrenia. The discovery provides a new potential therapeutic target.

Schizophrenia is a lifelong brain disorder that affects 1% of adults worldwide. Symptoms, which begin in late adolescence or early adulthood, include delusions such as hearing voices and seeing hallucinations, paranoia and depression. Schizophrenia affects attention, memory and organization.

It's unclear what causes schizophrenia. Studies suggest that the disease stems from complex interactions between multiple genes and environmental factors. Several candidate genes have recently been statistically linked to the illness. Scientists at NIH's National Institute of Mental Health (NIMH), National Institute on Child Health and Human Development (NICHD) and their European colleagues set out to follow these leads using 5 large clinical data sets with hundreds of families. The research team analyzed tiny variations called single nucleotide polymorphisms (SNPs) that had already been linked to schizophrenia in previous studies.

In the May 2009 edition of Nature Medicine, the researchers reported that their analysis pinpointed 4 variations in a small region of a gene called KCNH2. The KCNH2 gene encodes a potassium channel, a type of protein that regulates the flow of potassium ions into or out of cells. KCNH2 is best known for its role in heart muscle, where it transports potassium ions out of cells, recharging the muscle after each heartbeat to maintain a regular rhythm.

In the brain, KCNH2 is known to be active primarily in the prefrontal cortex and hippocampus. These areas are important for attention and memory. In neurons, potassium channels help control when the cells fire to signal neighboring neurons. The process is partly regulated by the chemical messenger dopamine, which is the main target of antipsychotic medications currently used to treat schizophrenia.

The researchers discovered that healthy people who carried the SNPs performed significantly worse on measures of IQ and mental processing. MRI scans revealed that their brains had excessive activity for the tasks being carried out—a phenomenon previously implicated in schizophrenia. Healthy people with the SNPs also had a smaller hippocampus, which has also been tied to schizophrenia.

Upon closer genetic analysis of the KCNH2 gene from 10 people with schizophrenia, the researchers discovered a new form of KCNH2, called Isoform 3.1. In healthy controls, the levels of Isoform 3.1 and KCNH2 in the hippocampus were about the same. However, the ratio of Isoform 3.1 to KCNH2 proved to be 2.5 higher in people with schizophrenia.

The researchers used cultured rat neurons to reveal that Isoform 3.1 caused overactive neuron discharges. In the brain, the researchers speculate, this could abnormally raise neuron and brain circuit activity to cause the symptoms of schizophrenia.

The researchers say that a treatment designed to target Isoform 3.1 might improve information processing in the brains of people with schizophrenia while avoiding heart-related side effects.