Disrupted-in-schizophrenia 1 functional polymorphisms and D2/D3 receptor availability: A [11C]-(+)-PHNO imaging study

The disrupted-in-schizophrenia 1 (DISC1) protein has been implicated in a range of biological mechanisms underlying chronic mental disorders such as schizophrenia. Schizophrenia is associated with abnormal striatal dopamine signalling, and all antipsychotic drugs block striatal dopamine 2/3 receptors (D(2/3)Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D-2 receptor (D2R) that inhibits agonist-induced D2R internalisation. Moreover, animal studies have found large striatal increases in the proportion of D2R receptors in a high affinity state ((D2R)-R-high) in DISC1 rodent models. Here, we investigated the relationship between the three most common polymorphisms altering the amino-acid sequence of the DISC1 protein (Ser704Cys (rs821616), Leu607Phe (rs6675281) and Arg264Gln (rs3738401)) and striatal D2/3R availability in 41 healthy human volunteers, using [C-11]-(+)-PHNO positron emission tomography. We found no association between DISC1 polymorphisms and D2/3R availability in the striatum and D2R availability in the caudate and putamen. Therefore, despite a direct interaction between DISC1 and the D2R, none of its main functional polymorphisms impact striatal D2/3R binding potential, suggesting DISC1 variants act through other mechanisms.