title: Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks.
abstract: 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)(158)methionine (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 Val(158)Met 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.
authors: Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy. a.bertolino@psichiat.uniba.it <a.bertolino@psichiat.uniba.it>
authors: Alessandro
authors: A
authors: Bertolino
authors: Annabella
authors: A
authors: Di Giorgio
authors: Giuseppe
authors: G
authors: Blasi
authors: Fabio
authors: F
authors: Sambataro
authors: Grazia
authors: G
authors: Caforio
authors: Lorenzo
authors: L
authors: Sinibaldi
authors: Valeria
authors: V
authors: Latorre
authors: Antonio
authors: A
authors: Rampino
authors: Paolo
authors: P
authors: Taurisano
authors: Leonardo
authors: L
authors: Fazio
authors: Raffaella
authors: R
authors: Romano
authors: Sofia
authors: S
authors: Douzgou
authors: Teresa
authors: T
authors: Popolizio
authors: Bhaskar
authors: B
authors: Kolachana
authors: Marcello
authors: M
authors: Nardini
authors: Daniel R
authors: DR
authors: Weinberger
authors: Bruno
authors: B
authors: Dallapiccola
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000098:blood supply / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008715:Methionine / Q000235:genetics; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic; D021641:Recognition, Psychology / Q000502:physiology*; D020080:Tandem Repeat Sequences / Q000235:genetics; D014633:Valine / Q000235:genetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen; D004298:Dopamine