COMT Genetic Reduction Produces Sexually Divergent Effects on Cortical Anatomy and Working Memory in Mice and Humans

Cereb Cortex. 2015 Sep;25(9):2529-41. doi: 10.1093/cercor/bhu053. Epub 2014 Mar 21.

Abstract

Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations.

Keywords: cognition; cortical thickness; dopamine; postero-parietal cortex; prefrontal cortex.

MeSH terms

  • Adolescent
  • Adult
  • Analysis of Variance
  • Animals
  • Association Learning / physiology
  • Brain Mapping
  • Catechol O-Methyltransferase / deficiency
  • Catechol O-Methyltransferase / genetics*
  • Cerebral Cortex / anatomy & histology*
  • Cerebral Cortex / cytology
  • Female
  • Genotype
  • Homeodomain Proteins / metabolism
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Maze Learning
  • Memory, Short-Term / physiology*
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Mutation / genetics
  • Neurons / metabolism
  • Nuclear Proteins / metabolism
  • Phosphopyruvate Hydratase / metabolism
  • Repressor Proteins / metabolism
  • Sex Characteristics*
  • Young Adult

Substances

  • Cux1 protein, mouse
  • Homeodomain Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Catechol O-Methyltransferase
  • Phosphopyruvate Hydratase