title: Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences.
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.
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Giniatullina
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Maroteaux
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Geerts
authors.affiliation: Sylics (Synaptologics BV), Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Koopmans
authors.affiliation: Sylics (Synaptologics BV), Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Loos
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Klaassen
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Chen
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: van der Schors
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van Nierop
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: K W
authors.initials: KW
authors.lastname: Li
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: W D
authors.initials: WD
authors.lastname: Altrock
authors.affiliation: Department of Clinical Genetics, Section Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L N
authors.initials: LN
authors.lastname: Cornelisse
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: R F
authors.initials: RF
authors.lastname: Toonen
authors.affiliation: Department of Clinical Genetics, Section Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: van der Sluis
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Stiedl
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Posthuma
authors.affiliation: Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A J
authors.initials: AJ
authors.lastname: Groffen
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Department of Clinical Genetics, Section Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: m.verhage@vu.nl.
authors.forename: M
authors.initials: M
authors.lastname: Verhage
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000235:genetics / Q000503:physiopathology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D065808:Prepulse Inhibition / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D009479:Neuropeptides; C498630:PCLO protein, human
keywords: Piccolo; active zone; major depression; mouse behavior