Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity

Autor: Jackie E. Lim, Neema Yazdani, Stacey L Kirkpatrick, Greta Sokoloff, Clarissa C. Parker, W. Evan Johnson, Riyan Cheng, Loren A. Kole, Camron D. Bryant, Eric R. Reed, Abraham A. Palmer, Ying Shen, Michael A. Guido
Přispěvatelé: Copenhaver, Gregory P
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
Cancer Research
Messenger
Genome-wide association study
Synaptic Transmission
Heterogeneous-Nuclear Ribonucleoproteins
Methamphetamine
Drug Abuse
Mice
Gene expression
Nuclear Receptor Subfamily 4
Group A
Member 2
2.1 Biological and endogenous factors
Aetiology
Genetics (clinical)
Group A
Genetics
Behavior
Animal
Dopaminergic
Substance Abuse
Adaptor Proteins
Chromosome Mapping
Mental Health
Chromosomal region
medicine.drug
Biotechnology
Research Article
Nuclear Receptor Subfamily 4
Member 2
Drug Abuse (NIDA Only)
lcsh:QH426-470
Quantitative Trait Loci
Congenic
Quantitative trait locus
Biology
Motor Activity
Behavioral and Social Science
medicine
Animals
Humans
RNA
Messenger
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Adaptor Proteins
Signal Transducing
Behavior
Animal
Dopaminergic Neurons
Human Genome
Signal Transducing
Neurosciences
Brain Disorders
lcsh:Genetics
Good Health and Well Being
MRNA Sequencing
RNA
Central Nervous System Stimulants
Developmental Biology
Genome-Wide Association Study
Zdroj: PLoS Genetics, Vol 11, Iss 12, p e1005713 (2015)
PLoS Genetics
PLoS genetics, vol 11, iss 12
ISSN: 1553-7404
1553-7390
Popis: Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512–50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)—a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes—heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10−15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders.
Author Summary Both genetic and environmental factors can powerfully modulate susceptibility to substance use disorders. Quantitative trait locus (QTL) mapping is an unbiased discovery-based approach that is used to identify novel genetic factors and provide new mechanistic insight into phenotypic variation associated with disease. In this study, we focused on the genetic basis of variation in sensitivity to the acute locomotor stimulant response to methamphetamine which is a behavioral phenotype in rodents that is associated with stimulated dopamine release and activation of the brain reward circuitry involved in addiction. Using brute force monitoring of recombination events associated with changes in behavior, we fortuitously narrowed the genotype-phenotype association down to just two genes that we subsequently targeted using a contemporary genome editing approach. The gene that we validated–Hnrnph1 –is an RNA binding protein that did not have any previously known function in psychostimulant behavior or psychostimulant addiction. Our behavioral data combined with our gene expression results provide a compelling rationale for a new line of investigation regarding Hnrnph1 and its role in neural development and plasticity associated with the addictions and perhaps other dopamine-dependent psychiatric disorders.
Databáze: OpenAIRE
Externí odkaz: