Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression

Abstract

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.

Genetics of human memory functions in healthy cohorts

“…Additional studies utilizing the candidate gene approach suggest a role for COMT (encoding catechol-O-methyltransferase), PRKCA (encoding protein kinase C, alpha), PCLO (encoding piccolo, which is involved in monoaminergic neurotransmission), and NR3C1 (encoding nuclear receptor subfamily 3, group C, member 1, i.e., the glucocorticoid receptor) in differential aversive memory capacity in healthy individuals [58,59 , [60][61][62].…”

Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences

“…The third most significant single nucleotide polymorphism (SNP, rs2522833) coded for a non-synonymous amino acid change (p.Ser4814Ala) in the C2A domain of Piccolo. The association with MDD was independently reproduced by others (Hek et al, 2010;Aragam et al, 2011;Woudstra et al, 2012Woudstra et al, , 2013Verbeek et al, 2013), although it was not replicated in the more recent and largest GWAS to date (Ripke et al, 2013). A recent replicate case-control study (Minelli et al, 2012) investigated depression-related personality traits in healthy subjects as a function of the PCLO rs2522833 genotype.…”

“…This study showed that rs2522833 homozygotes were more frequent among MDD patients than in controls (p < 0.01). Minor allele carriers appeared to have increased vulnerability to depression, including higher harm avoidance and lower novelty seeking (more fearful and fatigable), altered emotional memory (Woudstra et al, 2013) and altered amygdala function during fearful facial processing (Woudstra et al, 2012). These findings provided further support for the involvement of the PCLO C2A domain in MDD pathogenesis, although the association was not always replicated in subsequent GWAS (Lewis et al, 2010;Muglia et al, 2010;Rietschel et al, 2010;Kohli et al, 2011;Shi et al, 2011;Shyn et al, 2011;Wray et al, 2012), and suggest that it may act by influencing personality traits that increase the risk of developing MDD.…”

No Evidence for the Association between a Polymorphism in the PCLO Depression Candidate Gene with Memory Bias in Remitted Depressed Patients and Healthy Individuals

“…In line with the Woudstra and colleagues [39] study, we also examined the two samples together. Because of their known effect on cognitive functioning and emotional processing, age and sex were included as covariates in the analyses.…”

“…Testing for Hardy–Weinberg equilibrium did not show deviation from the expected distribution of genotypes in healthy individuals, N = 351, χ 2  = .10, df = 1, p  = .75, nor in remitted patients, N = 320, χ 2  = .03, df = 1, p  = .85. Genotype groups were created in line with Woudstra and colleagues [39] and the association with depression: ‘C’ risk allele carriers (homozygous and heterozygous for C allele) versus ‘A’ non-risk allele carriers (homozygous for A allele).…”