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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. 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.

SUBMITTER: Drgonova J

PROVIDER: S-EPMC4749486 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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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.

Drgonova Jana J Walther Donna D Wang Katherine J KJ Hartstein G Luke GL Lochte Bryson B Troncoso Juan J Uetani Noriko N Iwakura Yoichiro Y Uhl George R GR

Molecular medicine (Cambridge, Mass.) 20150714 1

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 polymorphi ...[more]

PMID: 26181631

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Project description:Study objectivesTo validate the Multiple Suggested Immobilization Test (m-SIT), a symptom-provocation test measuring restless legs syndrome (RLS) severity multiple times a day while the patient is awake and resting under controlled conditions. The m-SIT was designed to overcome some limitations in measuring RLS severity with rating scales.DesignPatients completed two m-SITs on 2 consecutive days while on 24-h dopaminergic medication. After treatment discontinuation, they completed one more m-SIT 3 days later. Controls performed only one m-SIT.SettingSleep laboratory.ParticipantsNineteen patients with RLS and 10 healthy controls.InterventionsThe original m-SIT consisted of seven modified 60-min SITs performed every 2 h between noon and midnight. During each SIT, the subject reclined quietly but could move his or her legs without restriction to alleviate symptoms. Every 10 min, periodic leg movements during wakefulness (PLMW) were evaluated and the m-SIT Disturbance Scale (m-SIT-DS; range 0-10) was completed.Measurements and resultsThe m-SIT, composed of 6:00pm, 8:00pm, 10:00pm, and 12:00pm SITs, discriminated patients from controls (mean m-SIT-DS: 2.68 ± 2.35 versus 0.08 ± 0.26; mean PLMW/h, P = 0.0001) and between treatment groups (on medication versus taken off medication; mean m-SIT-DS, P = 0.0001; mean PLMW/h, P < 0.01). It proved reliable on retest and covariated well with the International Restless Legs Scale (IRLS) and scales measuring daytime symptoms (Spearman ? > 0.4).ConclusionsThe m-SIT is a valid and reliable test to evaluate RLS severity and treatment response, and could be useful in the future to confirm diagnosis and identify daytime symptoms. Although it was primarily designed for clinical trials, it might be useful in clinical settings because it provides a standardized testing condition to measure RLS symptoms.CitationGarcia-Borreguero D; Kohnen R; Boothby L; Tzonova D; Larrosa O; Dunkl E. Validation of the Multiple Suggested Immobilization Test: a test for the assessment of severity of restless legs syndrome (Willis-Ekbom disease). SLEEP 2013;36(7):1101-1109.

Dataset Information

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.

Publications

Mouse Model for Protein Tyrosine Phosphatase D (<i>PTPRD</i>) Associations with Restless Leg Syndrome or Willis-Ekbom Disease and Addiction: Reduced Expression Alters Locomotion, Sleep Behaviors and Cocaine-Conditioned Place Preference.

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