Journal article
Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity
PLoS genetics, Vol.11(12), pp.e1005713-e1005713
12/2015
DOI: 10.1371/journal.pgen.1005713
PMCID: PMC4675533
PMID: 26658939
Abstract
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.
Details
- Title: Subtitle
- Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity
- Creators
- Neema Yazdani - Boston UniversityClarissa C Parker - University of ChicagoYing Shen - Boston UniversityEric R Reed - Boston UniversityMichael A Guido - University of ChicagoLoren A Kole - University of ChicagoStacey L Kirkpatrick - Boston UniversityJackie E Lim - University of ChicagoGreta Sokoloff - University of ChicagoRiyan Cheng - University of ChicagoW Evan Johnson - Boston UniversityAbraham A Palmer - University of ChicagoCamron D Bryant - Boston University
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.11(12), pp.e1005713-e1005713
- DOI
- 10.1371/journal.pgen.1005713
- PMID
- 26658939
- PMCID
- PMC4675533
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science
- Grant note
- R01HG005692 / NHGRI NIH HHS T32 GM008541 / NIGMS NIH HHS R01DA021336 / NIDA NIH HHS R01 DA021336 / NIDA NIH HHS T32GM008541 / NIGMS NIH HHS R00DA029635 / NIDA NIH HHS R01 HG005692 / NHGRI NIH HHS R01DA039168 / NIDA NIH HHS R01 DA039168 / NIDA NIH HHS U01 HD043430 / NICHD NIH HHS R00 DA029635 / NIDA NIH HHS
- Language
- English
- Date published
- 12/2015
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984256929502771
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