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

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• The disrupted-in-schizophrenia 1 (DISC1) protein is linked to schizophrenia pathogenesis and interacts with dopamine D2 receptors (D2R).
• Schizophrenia involves abnormal striatal dopamine signaling, and antipsychotics target dopamine D2/3 receptors (D2/3 Rs).
• DISC1 and D2R interaction inhibits D2R internalization, and DISC1 models show altered D2R states.

Purpose of the Study:

• To investigate the association between common DISC1 protein polymorphisms and striatal D2/3 R availability in healthy humans.
• To determine if specific DISC1 genetic variants influence dopamine receptor binding potential in the brain.

Main Methods:

• Examined three common DISC1 amino-acid altering polymorphisms (Ser704Cys, Leu607Phe, Arg264Gln).
• Utilized [11C]-(+)-PHNO positron emission tomography in 41 healthy volunteers.
• Assessed striatal D2/3 R availability, including in the caudate and putamen.

Main Results:

• No significant association was found between the studied DISC1 polymorphisms and striatal D2/3 R availability.
• Specific DISC1 variants did not impact D2R availability in the caudate or putamen.
• The direct interaction between DISC1 and D2R does not appear to be modulated by these common DISC1 polymorphisms in humans.

Conclusions:

• Common functional DISC1 polymorphisms do not alter striatal D2/3 R binding potential in healthy individuals.
• DISC1's role in schizophrenia may involve mechanisms independent of its direct impact on striatal dopamine receptor availability.
• Further research is needed to elucidate the precise pathways through which DISC1 variants contribute to mental disorders.