Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks.
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.
Bertolino
Alessandro
A
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>
Di Giorgio
Annabella
A
Blasi
Giuseppe
G
Sambataro
Fabio
F
Caforio
Grazia
G
Sinibaldi
Lorenzo
L
Latorre
Valeria
V
Rampino
Antonio
A
Taurisano
Paolo
P
Fazio
Leonardo
L
Romano
Raffaella
R
Douzgou
Sofia
S
Popolizio
Teresa
T
Kolachana
Bhaskar
B
Nardini
Marcello
M
Weinberger
Daniel R
DR
Dallapiccola
Bruno
B
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
D050483:Dopamine Plasma Membrane Transport Proteins; D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen; D004298:Dopamine