Epistasis between Dopamine Regulating Genes Identifies a Nonlinear Response of the Human Hippocampus During Memory Tasks

Alessandro Bertolino, Annabella Di Giorgio, Giuseppe Blasi, Fabio Sambataro, Grazia Caforio, Lorenzo Sinibaldi, Valeria Latorre, Antonio Rampino, Paolo Taurisano, Leonardo Fazio, Raffaella Romano, Sofia Douzgou, Teresa Popolizio, Bhaskar Kolachana, Marcello Nardini, Daniel R. Weinberger, Bruno Dallapiccola

Research output: Contribution to journalArticlepeer-review


Background: Dopamine modulation of neuronal activity in prefrontal cortex maps to an inverted U-curve. Dopamine is also an important factor in regulation of hippocampal mediated memory processing. Here, we investigated the effect of genetic variation of dopamine inactivation via catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) on hippocampal activity in healthy humans during different memory conditions. Methods: Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 82 subjects matched for a series of demographic and genetic variables, we studied the effect of the COMT valine (Val)158methionine (Met) and the DAT 3′ variable number tandem repeat (VNTR) polymorphisms on function of the hippocampus during encoding of recognition memory and during working memory. Results: Our results consistently demonstrated a double dissociation so that DAT 9-repeat carrier alleles modulated activity in the hippocampus in the exact opposite direction of DAT 10/10-repeat alleles based on COMT Val158Met genotype during different memory conditions. Similar results were evident in ventrolateral and dorsolateral prefrontal cortex. Conclusions: These findings suggest that genetically determined dopamine signaling during memory processing maps to a nonlinear relationship also in the hippocampus. Our data also demonstrate in human brain epistasis of two genes implicated in dopamine signaling on brain activity during different memory conditions.

Original languageEnglish
Pages (from-to)226-234
Number of pages9
JournalBiological Psychiatry
Issue number3
Publication statusPublished - Aug 1 2008


  • Dopamine
  • encoding
  • hippocampus
  • prefrontal cortex
  • working memory

ASJC Scopus subject areas

  • Biological Psychiatry


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