Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences. (6th August 2015)

• Record Type: Journal Article
• Authors: Giniatullina, A.; Maroteaux, G.; Geerts, C.J.; Koopmans, B.; Loos, M.; Klaassen, R.; Chen, N.; van der Schors, R.C.; van Nierop, P.; Li, K.W.; de Jong, J.; Altrock, W.D.; Cornelisse, L.N.; Toonen, R.F.; van der Sluis, S.; Sullivan, P.F.; Stiedl, O.; Posthuma, D.; Smit, A.B.; Groffen, A.J.; Verhage, M.
• Is Part Of: Neuroscience. Volume 300(2015)
• Page Start: 518
• Page End: 538
• Publication Date: 2015-08-06
• Subjects: ANOVA analysis of variance -- CAZ cytomatrix at the active zone -- CS conditioned stimulus -- DIV days in vitro -- EGTA ethylene glycol tetraacetic acid -- EPM elevated plus maze -- EPSC excitatory postsynaptic current -- ES embryonic stem -- FDR false discovery rate -- FST forced swim test -- GST Glutathione S transferase -- GWAS genome-wide association study -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- MDD major depressive disorder -- PBS phosphate-buffered saline -- PCLO coding for Piccolo protein -- PPI prepulse inhibition -- RRP readily releasable pool -- RT room temperature -- SNP single nucleotide polymorphism -- US unconditioned stimulus; major depression -- mouse behavior -- Piccolo -- active zone; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.05.047
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Knock-in mouse carries PCLO gene variant associated with major depressive disorder. Synaptic Piccolo levels and synaptic transmission are increased in p.Ser4814Ala mice. Cellular phenotype does not translate into altered behavioral phenotype. Abstract: Genome-wide association studies have suggested a role for a genetic variation in the presynaptic gene PCLO in major depressive disorder (MDD). As with many complex traits, the PCLO variant has a small contribution to the overall heritability and the association does not always replicate. One variant (rs2522833, p.Ser4814Ala) is of particular interest given that it is a common, nonsynonymous exon variant near a calcium-sensing part of PCLO. It has been suggested that the molecular effects of such variations penetrate to a variable extent in the population due to phenotypic and genotypic heterogeneity at the population level. More robust effects may be exposed by studying such variations in isolation, in a more homogeneous context. We tested this idea by modeling PCLO variation in a mouse knock-in model expressing the Pclo SA / SA variant. In the highly homogeneous background of inbred mice, two functional effects of the SA-variation were observed at the cellular level: increased synaptic Piccolo levels, and 30% increased excitatory synaptic transmission in cultured neurons. Other aspects of Piccolo function were unaltered: calcium-dependent phospholipid binding, synapse formation in vitro, and synaptic accumulation of synaptic vesicles . Moreover, anxiety, cognition and depressive-like behavior were normal in Pclo SA / SA mice. We conclude that the PCLO p.Ser4814Ala missense variant produces mild cellular phenotypes, which do not translate into behavioral phenotypes. We propose a model explaining how (subtle) cellular phenotypes do not penetrate to the mouse behavioral level but, due to genetic and phenotypic heterogeneity and non-linearity, can produce association signals in human population studies.