Mouse Model for Protein Tyrosine Phosphatase D (PTPRD) Associations with Restless Leg Syndrome or Willis-Ekbom Disease and Addiction: Reduced Expression Alters Locomotion, Sleep Behaviors and Cocaine-Conditioned Place Preference
The receptor type protein tyrosine phosphatase D (PTPRD) gene encodes a cell adhesion molecule likely to influence development and connections of addiction-, locomotion- and sleep-related brain circuits in which it is expressed. The PTPRD gene harbors genome-wide association signals in studies of restless leg syndrome (Willis-Ekbom disease (WED)/restless leg syndrome (RLS); p < 10−8) and addiction-related phenotypes (clusters of nearby single nucleotide polymorphisms (SNPs) with 10−2 > p > 10−8 associations in several reports). We now report work that seeks (a) association between PTPRD genotypes and expression of its mRNA in postmortem human brains and (b) RLS-related, addiction-related and comparison behavioral phenotypes in hetero- and homozygous PTPRD knockout mice. We identify associations between PTPRD SNPs and levels of PTPRD mRNA in human brain samples that support validity of mouse models with altered PTPRD expression. Knockouts display less behaviorally defined sleep at the end of their active periods. Heterozygotes move more despite motor weakness/impersistence. Heterozygotes display shifted dose-response relationships for cocaine reward. They display greater preference for places paired with 5 mg/kg cocaine and less preference for places paired with 10 or 20 mg/kg. The combined data provide support for roles for common, level-of-expression PTPRD variation in locomotor, sleep and drug reward phenotypes relevant to RLS and addiction. Taken together, mouse and human results identify PTPRD as a novel therapeutic target for RLS and addiction phenotypes.
This work was supported by the NIH-IRP, NIDA, U.S. Department of Health and Human Services (HHS) (GR Uhl) and by New Mexico VA Health Care System (NMVAHCS) (GR Uhl). We are grateful for help from C Johnson, D Arking, D Naimen, J Bader and J Schroder; for access to brain samples from the University of Maryland Brain Tissue Bank; and for access to data for PTPRD from A Hart and A Palmer. All human and/or animal studies were approved by the appropriate institutional committees.
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