Schizophrenia-Related Gene Linked to Imbalance in Dopamine Pathways

December 17, 2007 • Science Update

Forms of a gene known to increase risk for schizophrenia may create an imbalance in brain pathways for dopamine, suggests a recent study by NIMH scientists. The findings could help explain how this key chemical messenger goes awry in the disorder, which affects about one percent of adults.

It has long been known that dopamine is overactive in schizophrenia and that some antipsychotic medications work by blocking the D2 subtype of dopamine receptor on neurons.

Geneticist Richard Straub, Ph.D., and colleagues in the NIMH Genes, Cognition and Psychosis Program, sought a mechanism for how a gene implicated in the illness might affect the number or sensitivity of D2 receptors.

Reported online November 7, 2007 in the Journal of Neuroscience, their findings hint at a genetically-influenced imbalance between the pathways mediating D2 and D1 dopamine receptors in schizophrenia.

Straub and colleagues had earlier linked to schizophrenia certain versions of a gene that results in reduced levels of a protein called dysbindin, which is involved in communications between brain cells. But how dysbindin might relate to dopamine remained a mystery.

To mimic what might occur in the brains of people with schizophrenia, the researchers reduced dysbindin levels in cultured rat neurons. Result: When stimulated with dopamine, the dysbindin-depleted neurons could no longer withdraw – or internalize – D2 receptors from the cell surface, as they usually do, to maintain balance and prevent over-simulation by the neurotransmitter. By contrast, lowering dysbindin levels had no such effect on neurons' ability to internalize D1 receptors.

The resulting imbalance between D2 and D1 pathways, thought to occur in schizophrenia, would presumably affect brain development and functioning of other neural systems, says Straub.

When the researchers reduced levels of another schizophrenia risk gene, called Muted, a protein that binds to dysbindin, they saw the same effect as when dysbindin itself was diminished. Out of 10 genes studied that operate in the same pathway as dysbindin, at least 4 – and probably 5 – are related to schizophrenia risk, according to the researchers.

Iizuka Y, Sei Y, Weinberger DR, Straub RE . Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization.J Neurosci. 2007 Nov 7;27(45):12390-5. PMID: 17989303

Schizophrenia-Related Gene Linked to Imbalance in Dopamine Pathways