Journal Article

Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity

Cheng, Riyan, Palmer, Abraham A., Reed, Eric R., Guido, Michael A., Sokoloff, Greta, Parker, Clarissa C., Lim, Jackie E., Johnson, W. Evan, Kirkpatrick, Stacey L., Bryant, Camron D., Shen, Ying, Yazdani, Neema, Kole, Loren A.

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - genetics / Addictions / Addictive behaviors / Amphetamine abuse / Animals / Attention Deficit Hyperactivity Disorder / Behavior / Behavior, Animal - drug effects / Central Nervous System Stimulants - administration & dosage / Chromosome Mapping / Dopamine / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Drug use / Funding / Gene expression / Genetic aspects / Genome-Wide Association Study / Genomes / Genotype & phenotype / Heterogeneous-Nuclear Ribonucleoproteins - genetics / Heterogeneous-Nuclear Ribonucleoproteins - metabolism / Humans / Male / Methamphetamine - administration & dosage / Mice / Motor Activity - drug effects / Motor Activity - genetics / Neurobiology / Neurosciences / Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics / Observations / Quantitative trait loci / Quantitative Trait Loci - genetics / RNA, Messenger - genetics / Schizophrenia / Synaptic Transmission - drug effects / Synaptic Transmission - genetics