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Comparison and Functional Genetic Analysis of Striatal Protein Expression Among Diverse Inbred Mouse Strains.

Cory Parks1, Francesco Giorgianni2, Byron C Jones1

  • 1Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States.

Frontiers in Molecular Neuroscience
|June 11, 2019
PubMed
Summary

Genetic differences in mouse striatum proteomes influence behavior. Comparing C57BL/6J and DBA/2J strains reveals significant protein variations linked to synaptic function and drug response.

Keywords:
C57BL/6JDBA/2JTHCmass spectrometryproteomicsstriatumsynaptosomesystems genetics

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Area of Science:

  • Neuroscience
  • Proteomics
  • Genetics

Background:

  • C57BL/6J (B6) and DBA/2J (D2) mouse strains exhibit significant genetic and behavioral differences.
  • These differences are particularly notable in striatal function, affecting behaviors like depression, anxiety, stress response, and drug responses.
  • The genetic underpinnings of these phenotypic variations remain largely uncharacterized.

Purpose of the Study:

  • To compare the striatal proteome between B6 and D2 mouse strains.
  • To correlate protein expression differences with mRNA levels and genetic variation.
  • To investigate whether differential protein expression contributes to observed behavioral differences between the strains.

Main Methods:

  • Proteomic analysis of membrane-enriched striatal fractions from B6 and D2 mice.
  • Comparison of protein expression data with corresponding mRNA levels.
  • Utilizing a BXD recombinant inbred population to study genetic regulation of mRNA and protein.
  • Validation of key protein expression differences and behavioral responses.

Main Results:

  • Over 2,500 proteins were identified in the striatum; 160 showed significant differential expression between B6 and D2 strains.
  • Key differentially expressed proteins include COMT, GABRA2, and cannabinoid receptor 1 (CNR1).
  • Overlap between protein and mRNA expression differences was 25%, increasing to 51% for genetically regulated transcripts.
  • Enrichment analysis revealed proteins involved in dopaminergic/glutamatergic synapses and synaptic plasticity (LTP/LTD).
  • Higher CNR1 expression in B6 striatum correlated with greater sensitivity to THC's locomotor effects.

Conclusions:

  • Significant differences exist in the striatal proteomes of B6 and D2 mice, potentially explaining behavioral variations.
  • Alterations in striatal proteome composition may underlie strain-specific responses to drugs of abuse.
  • Genetic variants influencing transcript levels are more likely to also impact protein expression, providing a link between genotype and phenotype.