Scientists link potassium flow with schizophrenia

An international team of scientists has identified a variant of a potassium channel that affects patients with schizophrenia. The results, published in the journal Nature Medicine, show how the expression of a formerly unknown form of a potassium channel is 2.5 times greater than normal in the brain memory hub of people suffering from this psychotic disorder, and is connected to a hotspot of genetic variation. Their findings could offer a new therapeutic target to combat schizophrenia.

The researchers found that selectively inhibiting this 'suspect form' (gene), could regulate disorganised brain activity in patients with schizophrenia without triggering the cardiac side effects commonly found with antipsychotic medications already on the market.

'The end game in linking genes with complex disorders like schizophrenia requires that we not only demonstrate statistical association, but also show how a gene version acts biologically to confer risk,' said Dr Daniel Weinberger of the National Institute of Mental Health's (NIMH) Genes Cognition and Psychosis Program. 'We found schizophrenia-like effects in brain circuitry and mental processing in perfectly healthy people who carry the risk-associated version of this potassium-channel gene, even though they don't show any psychotic behaviour,' the study leader added.

Past studies have hinted that schizophrenia is the result of complex interactions between multiple genes and environmental factors. Scientists have also statistically linked a number of candidate genes to the disorder in large genome-wide association studies.

'Our study goes further, spanning discovery of a new gene variant, confirmation of its association with the illness, and multi-level probes into how it works in human post-mortem brain tissue, the living human brain and neurons,' Dr Weinberger explained.

When the flow of potassium ions into the cell is regulated, the potassium channels are able to control when neurons fire, the scientists explain. The activity of the neurotransmitter dopamine regulates the potassium flow. Dopamine, the researchers say, is the main target of antipsychotic medications currently used to treat schizophrenia.

The KCNH2 potassium channel could sustain the type of neuronal firing that supports the higher mental functions that are interrupted in patients with schizophrenia. The team assessed the gene's association with schizophrenia in five independent samples comprising hundreds of families. Their analysis identified four variations that were linked with the disorder within a small region of the KCNH2 gene.

'Yet this statistical association didn't imply a mechanism,' Dr Weinberger noted. 'It didn't explain how KCNH2 might increase risk for schizophrenia. So we went back to the post-mortem brain tissue in search of an answer.'

The researchers established that 'Isoform 3.1', a previously unknown version of KCNH2, increased to levels 2.5 times higher in the hippocampus of patients with the illness than in unaffected subjects. 'Isoform 3.1 was also higher than normal in healthy individuals who carried the risk-associated variations,' the research showed. The outcome pointed to the existence of a version of the KCNH2 gene that was associated with risk for schizophrenia.