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

TY - JOUR

T1 - Disrupted-in-schizophrenia 1 functional polymorphisms and D2/D3 receptor availability

T2 - A [11C]-(+)-PHNO imaging study

AU - Dahoun, Tarik

AU - Nour, Matthew M.

AU - Adams, Rick A.

AU - Trossbach, Svenja

AU - Lee, Sang H.

AU - Patel, Hamel

AU - Curtis, Charles

AU - Korth, Carsten

AU - Howes, Oliver D.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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 (D2/3Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D2 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 (D2highR) 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 [11C]-(+)-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.

AB - 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 (D2/3Rs). Importantly, the DISC1 protein directly interacts and forms a protein complex with the dopamine D2 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 (D2highR) 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 [11C]-(+)-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.

KW - Arg264Gln

KW - DISC1

KW - dopamine

KW - Leu607Phe

KW - PET

KW - PHNO

KW - polymorphism

KW - psychosis

KW - receptor

KW - Ser704Cys

UR - http://www.scopus.com/inward/record.url?scp=85068432815&partnerID=8YFLogxK

U2 - 10.1111/gbb.12596

DO - 10.1111/gbb.12596

M3 - Article

AN - SCOPUS:85068432815

SN - 1601-1848

VL - 18

JO - Genes, Brain and Behavior

JF - Genes, Brain and Behavior

IS - 8

M1 - e12596

ER -