University of Groningen Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression Woudstra,

Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD. Citation: Woudstra S, van Tol M-J, Bochdanovits Z, van der Wee NJ, Zitman FG, et al. (2013) Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression. PLoS ONE 8(4): e61494. doi:10.1371/journal.pone. 0061494 Editor: Katharina Domschke, University of Wuerzburg, Germany Received November 5, 2012; Accepted March 10, 2013; Published April 19, 2013 Copyright: 2013 Woudstra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations: VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL), Netherlands Institute of Mental Health and Addiction (Trimbos Institute), the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL), and VU University’s institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA). The genotyping of the samples was provided through the Genetic Association Information Network (GAIN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: N.J.A. van der Wee received speaking fees from Eli Lilly and Wyeth and served on advisory panels of Eli Lilly, Pfizer, Wyeth, and Servier. A. Aleman received an investigator-initiated unrestricted research grant from Brystol-Myers Squibb and speakers bureau honoraria from AstraZeneca, Brystol-Myers Squibb, and GlaxoSmithKline. W.J. Hoogendijk lectured and advised for, and received unrestricted research grants from, Eli Lilly, Lundbeck, Servier, Bristol-Myers Squibb, and Organon for which payments were made to the independent research foundation of GGZ inGeest. W.J. Hoogendijk holds the following patent for gene-expression profiling in peripheral blood as a biomarker for depression (Name: Means and methods for typing a cell isolate of an individual suffering from a psychiatric disorder or at risk of suffering there from; Number: PCT/NL2008/050837; Date: December 19, 2008 [19.12.2008]). There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: s.woudstra@vumc.nl