title: 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.
abstract: 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. ThePTPRDgene 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> 10-8associations in several reports). We now report work that seeks (a) association betweenPTPRDgenotypes and expression of its mRNA in postmortem human brains and (b) RLS-related, addiction-related and comparison behavioral phenotypes in hetero- and homozygousPTPRDknockout mice. We identify associations betweenPTPRDSNPs and levels ofPTPRDmRNA in human brain samples that support validity of mouse models with alteredPTPRDexpression. 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 identifyPTPRDas a novel therapeutic target for RLS and addiction phenotypes.
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.
authors.forename: Jana
authors.initials: J
authors.lastname: Drgonova
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Walther
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.
authors.forename: G Luke
authors.initials: GL
authors.lastname: Hartstein
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.
authors.forename: Bryson
authors.initials: B
authors.lastname: Lochte
authors.affiliation: Division of Neuropathology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Troncoso
authors.affiliation: Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Canada.
authors.forename: Noriko
authors.initials: N
authors.lastname: Uetani
authors.affiliation: Center for Experimental Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Molecular Neurobiology Branch, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH)-Intramural Research Program (IRP), Baltimore, Maryland, United States of America.|Research, New Mexico VA Health Care System, Albuquerque, New Mexico, United States of America.
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl