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

A. Giniatullina, G.P. Maroteaux, C.J. Geerts, B. Koopmans, M. Loos, R.V. Klaassen, N. Chen, R.C. van der Schors, P. van Nierop, K.W. Li, A.P.H. de Jong, W.D. Altrock, L.N. Cornelisse, R.F.G. Toonen, S. van der Sluis, P.F. Sullivan, O. Stiedl, D. Posthuma, A.B. Smit, A.J.A. GroffenM. Verhage

Research output: Contribution to JournalArticleAcademicpeer-review

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 PcloSA/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 PcloSA/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.
Original languageEnglish
Pages (from-to)518-538
JournalNeuroscience
Volume300
DOIs
Publication statusPublished - 2015

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