COMT genetic reduction produces sexually divergent effects on cortical anatomy and working memory in mice and humans

Sara Sannino, Alessandro Gozzi, Antonio Cerasa, Fabrizio Piras, Diego Scheggia, Francesca Managò, Mario Damiano, Alberto Galbusera, Lucy C. Erickson, Davide De Pietri Tonelli, Angelo Bifone, Sotirios A. Tsaftaris, Carlo Caltagirone, Daniel R. Weinberger, Gianfranco Spalletta, Francesco Papaleo

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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 sexspecific 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.

Original languageEnglish (US)
Pages (from-to)2529-2541
Number of pages13
JournalCerebral Cortex
Issue number9
StatePublished - Sep 1 2015


  • Cognition
  • Cortical thickness
  • Dopamine
  • Postero-parietal cortex
  • Prefrontal cortex

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience


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